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The role of human bromodomains in chromatin

various histone modifications, lysine acetylation [4] is the most dynamic as this modification

directs both structural changes to chromatin and gene transcription [5–7].

The dynamic role of lysine acetylation in gene transcription is, to some extent, a result of the bromodomain (BRD), which is the only protein domain known to act as a acetyl-lysine binding domain [8]. BRD-containing proteins have also been implicated in disease processes, including cancer, inflammation and viral replication. This review describes the structural and functional features of human BRDs in chromatin biology and gene transcription.The bromodomain fold and acetyl-lysine recognition The available structures of the BRD from the human transcriptional co-activator PCAF (p300/CREB-binding protein-associated factor) [9,10] and the BRDs from the transcriptional protein TAF1 (transcription initiation factor TFIID subunit 1) [11] reveal that the BRDs of the histone acetyltransferase GCN5 [12,13], the co-activator CBP (CREB binding protein) [14], the BET family protein BRD2 [15], BPTF (the BRD and plant homeodomain [PHD] finger-containing transcription factor) [16] and the SNF2L4 (a SWI/SNF remodeling complex protein) [17] all adopt a distinct structural fold of a left-handed four-helix bundle (αZ , αA , αB and αC ), termed the `BRD fold'. The inter-helical αZ -αA (ZA)and αB -αC (BC) loops constitute a hydrophobic pocket that recognizes the acetyl-lysine (Figure 1A). Notably, the structural features of BRD/acetyl-lysine binding are significantly different to those of chromodomain/methyl-lysine binding, in which a methyl-lysine sequence forms an anti-parallel β-strand to the β-barrel structure of the chromodomain [18,19]. The modular nature of the BRD fold enables the BRD to act as a functional unit within a protein, either individually or in combination with other modules.Despite the structurally conserved BRD fold, the overall sequence similarity between members of the BRD family is not high, and there are significant variations in the sequences

of the ZA and BC loops [20]. Nevertheless, the amino acid residues that are engaged in

acetyl-lysine recognition are among the most conserved residues in the large BRD family,

and correspond to Tyr 1125, Tyr 1167 and Asn 1168 in CBP (Figure 1B) [14,21]. The crystal

structure of the yeast GCN5 BRD bound to a histone H4 peptide containing acetylated-

Lys 16 identified that, in addition to binding to the conserved Tyr 364 and Tyr 406 residues

(corresponding to Tyr 1125 and Tyr 1167 in CBP, respectively), the acetyl-lysine residue forms

a specific hydrogen-bond between the oxygen of the acetyl carbonyl group and the side-

chain amide nitrogen of the conserved asparagine residue, Asn 407 (corresponding to Asn 1168

in CBP) [13]. A network of water-mediated hydrogen bonds involving carbonyl groups from

the protein backbone at the base of the binding pocket also contributes to acetyl-lysine

binding. The critical role of these three conserved amino acid residues in acetyl-lysine

recognition has been confirmed by mutagenesis studies [9,10,14], and data demonstrate that

most of the BRD family members function as acetyl-lysine binding domains [9].

Significantly, the key Asn 1168 residue in CBP (Asn 407 in GCN5) is not present in a small

subgroup of BRDs, such as that of the transcriptional corepressor TIF1β (transcription

intermediate factor 1β) or the sixth BRD in the human Polybromo protein. The former BRD

does not bind to lysine-acetylated histones [22], whereas the latter BRD does [Zhou MM:

unpublished data], suggesting that there may be another mode of acetyl-lysine binding to the

conserved BRD fold.

The human bromodomain family

The human genome encodes 42 BRD-containing proteins, each of which contains between

one and six BRDs [23]. The total number of unique individual human BRDs is 56 (2 human

proteins, which contain 2 BRDs each, are both annotated as BRD2 and share > 99%

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sequence identity; their corresponding BRDs are identical in sequence [23]). These numbers can be contrasted with those of BRDs in the yeast genome, which encodes only nine BRD-containing proteins with a total of 14 BRDs [23]. The structural diversity of the human BRD family can be examined indirectly by clustering the 56 BRD sequences into groups that share similar sequence length and at least 35% sequence identity [24]. This yields nine groups, each of which contains at least two BRDs and eight outliers (see Table 1).The dominant BRD group has 24 members, including the BRDs of several double-BRD-containing proteins such as BRD2, BRD3, BRD4, the TFIID (transcription initiation factor)210-kDa subunit, TAF1 (the TFIID 250-kDa subunit) and the testis-specific protein BRDT [Sanchez R: unpublished data]. The same group includes BRDs from single-BRD-containing proteins such as the histone acetyltransferases PCAF and GCN5, TIF1α, TIF1γ,tripartite motif-containing protein 66, protein kinase C-binding protein 1 (Rack7), BAZ2A (BRD adjacent to zinc finger domain protein 2A), BAZ2B, BRD PHD finger transcription factor isoform 2, and the nuclear proteins Sp100, Sp110 and Sp140 [Sanchez R: unpublished data]. The structures of several proteins in this group have been solved [9,11,12,16]. The RIKEN Structural Genomics/Proteomics Initiative (RSGI) [25,26] and the Structural Genomics Consortium (SGC) [26] have determined the structures of the BRDs of BRD2,BRD3, BRD4, BRDT, TIF1α and BAZ2B. Huang et al determined the solution-state structure of the second BRD of BRD2 and demonstrated that this BRD is monomeric in solution and interacts dynamically with the acetylated Lys 12 residue of histone H4 [27].The second BRD group includes the BRDs of SNF2L2 and Brg-1, and the second, fourth and fifth BRDs of the Polybromo protein. The RSGI and the SGC have determined structures for the SNF2L2 BRD and the fifth BRD of the Polybromo protein [26,28], and research groups at two laboratories recently determined the structure of the Brg-1 BRD [17,29]. Shen et al used a solution structure and data from NMR perturbation studies to demonstrate that the Brg-1 BRD interacts with an H3K14ac peptide [17]. A crystal structure

of the same domain exhibited an unusual small β-sheet in the ZA loop [29].

The third group of human BRD-containing proteins includes BRD7 and BRD9, as well as

three proteins that contain a PHD in addition to BRDs. Sun et al reported a solution structure

for the BRD7 BRD, and used NMR and titration analysis with several acetylated histone

peptides to demonstrate that this BRD lacks inherent histone binding specificity in vitro

[30]. The RSGI determined the BRD structure of HOTTL (tubulin-tyrosine ligase-like

protein 3), one of the BRD and PHD containing proteins [28].

The next two groups of human BRDs correspond to the N-terminal and C-terminal BRDs of

three BRD- and tryptophan-aspartate (WD)-repeat-containing proteins, respectively

[Sanchez R: unpublished data]. No experimentally determined structures were available for

these six proteins.

The remaining four groups of human BRDs contain pairs of similar BRDs: the BRDs of

ATAD2 (ATPase family AAA domain-containing protein 2; ANCCA) and ATAD2B, the

structures of which were determined by the RSGI and the SGC [26,28]; the first and third

BRDs of human Polybromo; the BRDs of CBP and p300 (solution [14] and crystallographic

(SGC) [26] structures were available for the BRD of CBP); and the two BRDs of BRD8.

The eight outliers in this classification of human BRDs correspond to the sixth BRD of

Polybromo, and the BRDs of the zinc finger proteins HRX/ALL-1, ASH1L (absent small

and homeotic disks protein 1 homolog), BAZ1B, BAZ1A, MYND (myeloid translocation

protein 8, Nervy, and DEAF-1) domain-containing protein 11, TIF1β and CECR2 (cat eye

syndrome critical region protein 2) [Sanchez R: unpublished data]. Of these BRDs, an

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experimentally determined structure was available for TIF1β, which formed a structural unit

with the adjacent PHD finger [22].

In total, the structures of 23 of the 56 human BRDs have been experimentally determined.Of the 33 BRDs without experimental structures, 21 share > 35% sequence identity with a protein of known structure, and it is therefore possible to construct reasonably accurate homology models for these BRDs [24]. Although these data represent a thorough coverage of the structures of the BRD family proteins, no structural information is available for 12 of the 56 human BRDs. The unique sequences of these 12 BRDs of unknown structure (which either have low overall sequence similarity or long insertions with respect to the sequences of proteins with known structures) may contain special structural or functional features that have not yet been observed in the better characterized BRDs. Additionally, although the structural description of the BRDs is almost complete, many more structures of BRD-ligand complexes are required to facilitate a detailed understanding of ligand-binding selectivity.The existence of tandem domains (BRD-BRD, PHD-BRD or BRD-PHD), which are tightly associated with each other in sequence and most likely also in the 3D structure, adds another level of complexity to the structural description of BRDs.The association of bromodomains with other chromatin modules BRDs are promiscuous domains in that they occur in a variety of proteins with different domain architectures, and can be considered functionally independent (ie, BRD-containing proteins do not all perform the same function) [31,32]. For example, the BRD-containing protein PCAF is a histone lysine acetyltransferase, whereas HRX/ALL-1 is a histone lysine N -methyltransferase and SNF2L2 is an ATP-dependent helicase. More than 15 different domain types have been identified to occur within the same proteins as BRDs, including the PHD, PWWP, B-box type zinc finger, ring finger, SAND, FY Rich, SET, TAZ zinc Finger,helicase, ATPase, BAH (bromo adjacent homolog) domain, WD40 repeat and MBD (methyl-CpG binding domain) [23].

The domain that is most frequently associated with the BRD is the PHD finger, which is a

C4HC3 zinc-finger-like motif present in nuclear proteins. A PHD has been identified in 19

of the 42 human BRD-containing proteins. In 12 of these proteins the PHD and BRD are

separated by a short amino acid sequence (< 30 residues) and may form structurally

interdependent tandem PHD/BRD arrangements such as those observed in TIF1β [22]. The

TIF1β structure contains a distinct scaffold that unifies the two protein modules, in which

the Z helix of the BRD forms a hydrophobic core that anchors the other three helices of the

BRD on one side and the PHD finger on the other. A comprehensive structure-function

analysis correlating transcriptional repression, UBC9 (ubiquitin-conjugating enzyme 9)

binding and SUMOylation demonstrated that the PHD finger and BRD of TIF1β cooperate

as a functional unit to facilitate lysine SUMOylation, which is required for TIF1β

corepressor activity in gene silencing [22,33]. These results identified a unified function for

the tandem PHD/BRD as an intramolecular SUMO E3 ligase for transcriptional silencing.

The ligase activity is a divergent function for the BRD, which does not bind to lysine-

acetylated histones in this form. In contrast to TIF1β, the structure of BPTF, which also

contains a PHD finger and a BRD separated by a short linker [16], did not demonstrate any

significant structural interactions between the two domains. In BPTF, the PHD domain

recognized the methylated Lys 4 residue of histone H3 (H3K4me3) [16,34]. However, the

histone binding specificity of the BPTF BRD was not established. These examples

demonstrate that not only do BRD-containing proteins vary significantly in function, but that

the BRD itself may have different binding activities as a consequence of other associated

domains.

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The second most common domain association for the BRD is an association with another

BRD; of the 42 BRD-containing proteins, 12 contain 2 or more BRDs. With the exception of

Polybromo, which contains six BRDs, all other proteins with multiple BRDs contain two

BRDs. In the transcription initiation factor TAF1 and TFIID 210-kDa subunits, as well as in

some of the Polybromo BRD pairs, the two BRDs are separated by short amino acid

sequences (< 20 residues). The structure of the TAF1 BRDs suggests that they form a

tandem arrangement that binds selectively to multiple acetylated histone H4 peptides [11].

Another tandem BRD arrangement was observed in the yeast Rsc4 protein, which is related

to human Polybromo [35]. The yeast Rsc4 structure contains a compact BRD tandem that

binds H3K14ac in the second BRD and the acetylated Lys 25 residue of Rsc4 itself in the first

BRD, suggesting an autoregulatory mechanism [35]. The arrangement of the tandem BRDs

in TAF1 and yeast Rsc4 are different; therefore, whether the arrangement of tandem BRDs

are protein-specific or are evolutionarily conserved is unclear. The structures of additional

putative tandem BRDs (such as those from Polybromo) will be necessary to fully elucidate

if BRD arrangements are evolutionarily conserved.

In human proteins, the association of BRDs with domains other than PHDs or BRDs occurs

infrequently. For example, BRDs can associate with either PWWP or B-box zinc finger

domains, but in each case these domains are present in only four human BRD-containing

proteins. Additionally, of the non-BRD domains that associate with BRDs, none occur in as

close proximity to a BRD within the protein sequence as either the PHD or BRDs that form

the tandem motifs [23]. The association between PHDs and BRDs often observed in human

proteins is absent in yeast, although yeast does express proteins that contain both BRDs and

PHDs [23].Functions of human bromodomain proteins The complexity and variability of the domain composition of human BRD-containing proteins, and the influence of neighboring domains (such as the PHD) on the function of the

BRD itself, make it difficult to predict the function of BRD-containing proteins based on

sequence similarity alone. Many of the human BRD-containing proteins do not have well-

characterized functions, although some have been implicated in disease processes. The most

recent data on human BRD-containing protein function and disease involvement are

reviewed in this section. However, the specific function of any of the BRDs remains to be

elucidated.

BRD4 plays an important role in various biological processes by means of its two BRDs.

This protein functions in the inflammatory response as a co-activator for the transcriptional

activation of NF κB, via the binding of the BRDs to the acetylated-Lys 310 residue on the

RelA subunit of NF κB [36]. BRD4 also plays a cellular role by stimulating G1 gene

transcription and promoting cell-cycle progression to the S phase [37]. Additionally, BRD4

can control the transcription of viral genes. For example, this protein regulates HIV

transcription by inducing the phosphorylation of CDK9 (cyclin-dependent kinase 9) at the

Thr 29 residue in the HIV transcription initiation complex, thereby inhibiting CDK9 kinase

activity and leading to the inhibition of HIV transcription [38]. BRD4 is also involved in the

inhibition of the proteasomal degradation of the papillomavirus E2 protein [39].

Furthermore, BRD4 associates with Kaposi's sarcoma-associated herpesvirus-encoded

LANA-1 (latency-associated nuclear antigen) through molecular interactions involving the

C-terminal region [40] and extraterminal domain [41] of BRD4. Additionally, both BRD4

and BRD2 interact with the murine γ-herpesvirus 68 protein or f73, which is required to

establish viral latency in vivo [42]. Finally, BRD4 activation may also predict the survival of

patients with breast cancer [43]. Crawford et al proposed that the activation of BRD4

manipulates the response of the tumor to its microenvironment in vivo , resulting in a

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reduction of tumor growth and pulmonary metastasis in mice [44]. Microarray analysis of

multiple human mammary tumor cell lines demonstrated that the activation of BRD4 was

predictive of progression and/or survival. These results suggest that the dysregulation of

BRD4-associated pathways may play an important role in breast cancer progression.

The coupling of histone acetylation to transcription in vivo by BRD2 and BRD3 was

demonstrated; in human 293 cells, these proteins preferentially associated with specific H4

modifications along the entire lengths of genes, and allowed RNA polymerase II to

transcribe through the nucleosomes [43]. BRD2 also exhibited histone chaperone activity

[43]. In mice, BRD2 is essential for embryonic development [45], and an association

between BRD2 and juvenile myoclonic epilepsy in humans has been reported [46].

In mice, the BRD and WD-repeat-containing protein BRWD1 is required for normal

spermiogenesis and the oocyte-embryo transition [47]. A mutation in BRWD1 leads to

phenotypically normal, but infertile mice.

The BRD of transcriptional co-activator p300 was suggested to play a role in the IL-6

signaling pathway, by mediating the interaction of the STAT3 amide-terminal domain with

p300, thereby stabilizing enhanceosome assembly [48].

ATAD2 is an estrogen-regulated ATPase co-activator with a BRD that functions in both

estrogen receptor α and androgen receptor signaling. This protein is required for the

formation of transcriptional coregulator complexes at chromatin and the modification of

chromatin [49]. Chen and colleagues suggested that ATAD2 plays an important role in

prostate cancer by mediating specific androgen receptor functions involved in cancer cell

survival and proliferation [50].Conclusion The role of the BRD as the sole protein domain known to recognize acetyl-lysine residues

on proteins is more complex than initially thought [9,11,51]. Studies of individual BRDs,

which have focused on the structural characterization of the domains and their interactions

with ligands, identified varied ligand-binding specificities that were dependent not only on

the characteristics of the BRD itself, but also on the other domains (BRD and non-BRD)

present in the same protein. Studies of BRD-containing proteins have highlighted the role of

these domains in many important biological processes and their association with disease.

The characterization of the multiplicity of molecular interactions mediated by BRDs is

therefore essential for deciphering the role of individual domains and proteins. This

challenging task may be facilitated by the high structural coverage of the human BRD

family, which presents a unique opportunity for the rational design of selective small

molecules that could serve as tools to modulate and control gene expression in the human

biology.

Acknowledgments

The authors were supported by the grants GM081713 (Roberto Sanchez), MCB0517352 (Ming-Ming Zhou/R

Sanchez), CA87658 and HG004508 (MM Zhou).

Abbreviations

ATAD

ATPase family AAA domain-containing protein BPTF BRD and PHD finger-containing transcription factor

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BRD bromodomain

CBP CREB binding protein

H histone

PCAF p300/CREB-binding protein-associated factor

PHD plant homeodomain

SUMO small ubiquitin-like modifier

TAF1transcription initiation factor TFIID subunit 1

TIF transcription intermediate factor

TFIID transcription initiation factor

WD tryptophan-aspartate

ZA αZ -αA References ?? of outstanding interest ? of special interest 1. Jenuwein T, Allis CD. Translating the histone code. Science 2001;293(5532):1074–1080. [PubMed:11498575]2. Turner BM. Cellular memory and the histone code. Cell 2002;111(3):285–291. [PubMed:12419240]3. Nightingale KP, O'Neill LP, Turner B. Histone modifications: Signalling receptors and potential

elements of a heritable epigenetic code. Curr Opin Genet Dev 2006;16(2):125–136. [PubMed:

16503131]

4. Allfrey VG, Faulkner R, Mirsky AE. Acetylation and methylation of histones and their possible role

in the regulation of RNA synthesis. Proc Natl Acad Sci USA 1964;51(5):786–794. [PubMed:

14172992]

5. Turner BM. Histone acetylation as an epigenetic determinant of long-term transcriptional

competence. Cell Mol Life Sci 1998;54(1):21–31. [PubMed: 9487384]

6. Berger SL. Histone modifications in transcriptional regulation. Curr Opin Genet Dev 2002;12(2):

142–148. [PubMed: 11893486]

7. Neely K, Workman J. Histone acetylation and chromatin remodeling: Which comes first? Mol

Genet Metab 2002;76(1):1–5. [PubMed: 12175774]

8. Zeng L, Zhou MM. Bromodomain: An acetyl-lysine binding domain. FEBS Lett 2002;513(1):124–

128. [PubMed: 11911891]

9. Dhalluin C, Carlson JE, Zeng L, He C, Aggarwal AK, Zhou MM. Structure and ligand of a histone

acetyltransferase bromodomain. Nature 1999;399(6735):491–496. [PubMed: 10365964]

10. Mujtaba S, He Y, Zeng L, Farooq A, Carlson JE, Ott M, Verdin E, Zhou MM. Structural basis of

lysine-acetylated HIV-1 Tat recognition by PCAF bromodomain. Mol Cell 2002;9(3):575–586.

[PubMed: 11931765]

11. Jacobson R, Ladurner AG, King DS, Tijan R. Structure and function of a human TAFII250 double

bromodomain module. Science 2000;288(5470):1422–1425. [PubMed: 10827952]

12. Hudson BP, Martinez-Yamout MA, Dyson HJ, Wright PE. Solution structure and acetyl-lysine

binding activity of the Gcn5 bromodomain. J Mol Biol 2000;304(3):355–370. [PubMed:

11090279]

NIH-PA Author Manuscript

13. Owen D, Ornaghi P, Yang JC, Lowe N, Evans PR, Ballario P, Neuhaus D, Filetici P, Travers AA.The structural basis for the recognition of acetylated histone H4 by the bromodomain of histone acetyltransferase Gcn5p. EMBO J 2000;19(22):6141–6149. [PubMed: 11080160]14. Mujtaba S, He Y, Zeng L, Yan S, Plotnikova O, Sachchidanand, Sanchez R, Zeleznik-Le NJ,Ronai Z, Zhou MM. Structural mechanism of the bromodomain of the coactivator CBP in p53transcriptional activation. Mol Cell 2004;13(2):251–263. [PubMed: 14759370]15. Nakamura Y, Umehara T, Nakano K, Jang MK, Shirouzu M, Morita S, Uda-Tochio H, Hamana H,Terada T, Adachi N, Matsumoto T, et al. Crystal structure of the human BRD2 bromodomain:Insights into dimerization and recognition of acetylated histone H4. J Biol Chem 2007;282(6):4193–4201. [PubMed: 17148447]16. Li H, Ilin S, Wang W, Duncan EM, Wysocka J, Allis CD, Patel DJ. Molecular basis for site-specific read-out of histone H3K4me3 by the BPTF PHD finger of NURF. Nature 2006;442(7098):91–95. [PubMed: 16728978]17. Shen W, Xu C, Huang W, Zhang J, Carlson JE, Tu X, Wu J, Shi Y. Solution structure of human Brg1 bromodomain and its specific binding to acetylated histone tails. Biochemistry 2007;46(8):2100–2110. [PubMed: 17274598]18. Nielsen P, Nietlispach D, Mott HR, Callaghan J, Bannister A, Kouzarides T, Murzin AG, Murzina NV, Laue ED. Structure of the HP1 chromodomain bound to histone H3 methylated at lysine 9.Nature 2002;416(6876):103–107. [PubMed: 11882902]19. Jacobs SA, Khorasanizadeh S. Structure of HP1 chromodomain bound to a lysine 9-methylated histone H3 tail. Science 2002;295(5562):2080–2083. [PubMed: 11859155]20. Jeanmougin F, Wurtz JM, Le Douarin B, Chambon P, Losson R. The bromodomain revisited.Trends Biochem Sci 1997;22(5):151–153. [PubMed: 9175470]21. Zeng L, Zhang Q, Gerona-Navarro G, Moshkina N, Zhou MM. Structural basis of site-specific histone recognition by the bromodomains of human coactivators PCAF and CBP/p300. Structure 2008;16(4):643–652. [PubMed: 18400184]22. Zeng L, Yap KL, Ivanov AV, Wang X, Mujtaba S, Plotnikova O, Rauscher FJ 3rd, Zhou MM.Structural insights into human KAP1 PHD finger-bromodomain and its role in gene silencing. Nat Struct Mol Biol 2008;15(6):626–633. [PubMed: 18488044] ?? The structure of a tandem PHD

finger-BRD reveals a tight structural and functional association between the two domains and a

new role for a BRD. The tandem facilitates the lysine SUMOylation required for gene silencing.

23. Schultz J, Copley RR, Doerks T, Ponting CP, Bork P. SMART: A web-based tool for the study of

genetically mobile domains. Nucleic Acids Res 2000;28(1):231–234. [PubMed: 10592234]

24. Sanchez R, Pieper U, Melo F, Eswar N, Martí-Renom MA, Madhusudhan MS, Mirkovi ? N, Sali A.

Protein structure modeling for structural genomics. Nat Struct Biol 2000;7(Suppl):986–990.

[PubMed: 11104007]

25. Yokoyama S, Terwilliger TC, Kuramitsu S, Moras D, Sussman JL. RIKEN aids international

structural genomics efforts. Nature 2007;445(7123):21. [PubMed: 17203040]

26. The Structural Genomics Consortium. University of Oxford; University of Toronto; Karolinska

Institutet; Oxford, UK: Toronto, ON, Canada: Stockholm, Sweden: 2009.

https://www.wendangku.net/doc/963287393.html,/index.php

27. Huang H, Zhang J, Shen W, Wang X, Wu J, Wu J, Shi Y. Solution structure of the second

bromodomain of BRD2 and its specific interaction with acetylated histone tails. BMC Struct Biol

2007;7:57. [PubMed: 17848202]

28. RIKEN Structural Genomics/Proteomics Initiative. RIKEN Genomic Sciences Center/RIKEN

SPring-8 Center; Yokohama, Japan: 2009. www.rsgi.riken.go.jp/rsgi_e/index.html

29. Singh M, Popowicz GM, Krajewski M, Holak TA. Structural ramification for acetyl-lysine

recognition by the bromodomain of human Brg1 protein, a central ATPase of the SWI/SNF

remodeling complex. Chembiochem 2007;8(11):1308–1316. [PubMed: 17582821]

30. Sun H, Liu J, Zhang J, Shen W, Huang H, Xu C, Dai H, Wu J, Shi Y. Solution structure of BRD7

bromodomain and its interaction with acetylated peptides from histone H3 and H4. Biochem

Biophys Res Commun 2007;358(2):435–441. [PubMed: 17498659]

31. Basu MK, Carmel L, Rogozin IB, Koonin EV. Evolution of protein domain promiscuity in

eukaryotes. Genome Res 2008;18(3):449–461. [PubMed: 18230802]

NIH-PA Author Manuscript

32. Basu MK, Poliakov E, Rogozin IB. Domain mobility in proteins: Functional and evolutionary implications. Brief Bioinform 2009;10(3):205–216. [PubMed: 19151098]33. Ivanov AV, Peng H, Yurchenko V, Yap KL, Negorev DG, Schultz DC, Psulkowski E, Fredericks WJ, White DE, Maul GG, Sadofsky MJ, et al. PHD domain-mediated E3 ligase activity directs intramolecular sumoylation of an adjacent bromodomain required for gene silencing. Mol Cell 2007;28(5):823–837. [PubMed: 18082607]34. Wysocka J, Swigut T, Xiao H, Milne TA, Kwon SY, Landry J, Kauer M, Tackett AJ, Chait BT,Badenhorst P, Wu C, Allis CD. A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling. Nature 2006;442(7098):86–90. [PubMed: 16728976]35. VanDemark AP, Kasten MM, Ferris E, Heroux A, Hill CP, Cairns BR. Autoregulation of the Rsc4tandem bromodomain by Gcn5 acetylation. Mol Cell 2007;27(5):817–828. [PubMed: 17803945]36. Huang B, Yang XD, Zhou MM, Ozato K, Chen LF. BRD4 coactivates transcriptional activation of NF-κB via specific binding to acetylated RelA. Mol Cell Biol 2009;29(5):1375–1387. [PubMed:19103749] ?? BRDs of BRD4 bind to the acetylated RelA subunit of NF κB, enhancing its transcriptional activation, and play a role in inflammatory response.37. Mochizuki K, Nishiyama A, Jang MK, Dey A, Ghosh A, Tamura T, Natsume H, Yao H, Ozato K.The bromodomain protein BRD4 stimulates G1 gene transcription and promotes progression to S phase. J Biol Chem 2008;283(14):9040–9048. [PubMed: 18223296]38. Zhou M, Huang K, Jung KJ, Cho WK, Klase Z, Kashanchi F, Pise-Masison CA, Brady JN.Bromodomain protein BRD4 regulates human immunodeficiency virus transcription through phosphorylation of CDK9 at threonine 29. J Virol 2009;83(2):1036–1044. [PubMed: 18971272]39. Gagnon D, Joubert S, Sénéchal H, Fradet-Turcotte A, Torre S, Archambault J. Proteasomal degradation of the papillomavirus E2 protein is inhibited by overexpression of bromodomain-containing protein 4. J Virol 2009;83(9):4127–4139. [PubMed: 19211738] ? Describes the role ofBRD4 in increasing levels of the E2 protein from human papillomavirus.40. Ottinger M, Christalla T, Nathan K, Brinkmann MM, Viejo-Borbolla A, Schulz TF. Kaposi's sarcoma-associated herpesvirus LANA-1 interacts with the short variant of BRD4 and releases cells from a BRD4- and BRD2/RING3-induced G1 cell cycle arrest. J Virol 2006;80(21):10772–10786. [PubMed: 16928766]

41. Lin YJ, Umehara T, Inoue M, Saito K, Kigawa T, Jang MK, Ozato K, Yokoyama S, Padmanabhan

B, Güntert P. Solution structure of the extraterminal domain of the bromodomain-containing

protein BRD4. Protein Sci 2008;17(12):2174–2179. [PubMed: 18815416]

42. Ottinger M, Pliquet D, Christalla T, Frank R, Stewart JP, Schulz TF. The interaction of the γ-

herpesvirus 68 orf73 protein with cellular BET proteins affects the activation of cell cycle

promoters. J Virol 2009;83(9):4423–4434. [PubMed: 19244327]

43. LeRoy G, Rickards B, Flint SJ. The double bromodomain proteins BRD2 and BRD3 couple

histone acetylation to transcription. Mol Cell 2008;30(1):51–60. [PubMed: 18406326] ?? Describes

how BRD2 and BRD3 bind to hyperacetylated chromatin of transcribed genes and allow RNA

polymerase II to transcribe through nucleosomes.

44. Crawford NP, Alsarraj J, Lukes L, Walker RC, Officewala JS, Yang HH, Lee MP, Ozato K,

Hunter KW. Bromodomain 4 activation predicts breast cancer survival. Proc Natl Acad Sci USA

2008;105(17):6380–6385. [PubMed: 18427120] ? The BRD4 activation signature, derived from

microarray analyses, is a good predictor of human breast cancer progression and patient survival.

45. Shang E, Wang X, Wen D, Greenberg DA, Wolgemuth DJ. Double bromodomain-containing gene

BRD2 is essential for embryonic development in mouse. Dev Dyn 2009;238(4):908–917.

[PubMed: 19301389]

46. Pal DK, Evgrafov OV, Tabares P, Zhang F, Durner M, Greenberg DA. BRD2 (RING3) is a

probable major susceptibility gene for common juvenile myoclonic epilepsy. Am J Hum Genet

2003;73(2):261–270. [PubMed: 12830434]

47. Philipps DL, Wigglesworth K, Hartford SA, Sun F, Pattabiraman S, Schimenti K, Handel M,

Eppig JJ, Schimenti JC. The dual bromodomain and WD repeat-containing mouse protein

BRWD1 is required for normal spermiogenesis and the oocyte-embryo transition. Dev Biol

2008;317(1):72–82. [PubMed: 18353305]

NIH-PA Author Manuscript

48. Hou T, Ray S, Lee C, Brasier AR. The STAT3 NH2-terminal domain stabilizes enhanceosome

assembly by interacting with the p300 bromodomain. J Biol Chem 2008;283(45):30725–30734.

[PubMed: 18782771] ? The N-terminal domain of STAT3 interacts with the p300 BRD in an

acetylation-dependent manner and stabilizes enhanceosome assembly. NIH-PA Author Manuscript

49. Zou JX, Revenko AS, Li LB, Gemo AT, Chen HW. ANCCA, an estrogen-regulated AAA+

ATPase coactivator for ERα, is required for coregulator occupancy and chromatin modification.

Proc Natl Acad Sci USA 2007;104(46):18067–18072. [PubMed: 17998543] ? The ATAD2 BRD-

containing protein interacts with the androgen receptor and enhances its transcriptional activity,

thus playing a role in prostate cancer. Suggests the ATPase and BRD of ATAD2 represent

potential new targets for prostate cancer therapeutics.

50. Zou JX, Guo L, Revenko AS, Tepper CG, Gemo AT, Kung HJ, Chen HW. Androgen-induced

coactivator ANCCA mediates specific androgen receptor signaling in prostate cancer. Cancer Res

2009;69(8):3339–3346. [PubMed: 19318566]

51. Mujtaba S, Zeng L, Zhou MM. Structure and acetyl-lysine recognition of the bromodomain.

Oncogene 2007;26(37):5521–5527. [PubMed: 17694091]

NIH-PA Author Manuscript

Figure 1. Structural basis of acetyl-lysine recognition by the bromodomain

(A ) The 3-D structure of the CREB binding protein (CBP) bromodomain (BRD) bound to a

H4K20ac peptide (PDB code: 2RNY); and (B ) the acetyl-lysine binding site, showing the

key interactions between the CBP BRD and a H4K20ac peptide. The peptide is yellow and

the side chains of the protein residues are color-coded by atom type.

NIH-PA Author Manuscript

NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript

Table 1

Classification of the human bromodomain family.

Group Bromodomains Reference 1PCAF, hGCN5, TIF1α, TIF1γ, TRI66, Rack7, BAZ2A, BAZ2B, NURF (isoform 2), Sp100, Sp110, Sp140,

BRD21, BRD22, BRD31, BRD32, BRD41, BRD42, TAFII2101, TAFII2102, TAF11, TAF12, BRDT1 and BRDT2

[9,11,12,16,27]* 2SNF2L2, SNF4L4, Polybromo2, Polybromo4 and Polybromo5[17,29]* 3BRD1, BRD7, BRD9, HOTTL and BRD and PHD finger-containing protein 3[30]* 4BRD 1 of BRD and WD-repeat-containing proteins 1, 2 and 3-5BRD 2 of BRD and WD-repeat-containing proteins 1, 2 and 3-6ATAD2 and ATAD2B* 7Polybromo1 and Polybromo3-8CBP and p300[14]* 9BRD81 and BRD82-Outliers Polybromo6, HRX/ALL-1, ASH1L, BAZ1B, BAZ1A, MYND11, TIF1β and CECR2[22]

All human BRDs are classified into nine groups, plus one additional set of outliers. The groups represent clusters that are based on 35% sequence identity. Individual BRDs within a multi-BRD protein are indicated by subscripts. BRDs for which experimentally determined structures are available are marked in bold.

ASH1L absent small and homeotic disks protein 1 homolog, ATAD ATPase family AAA domain-containing protein, BAZ BRD adjacent to zinc finger domain protein, BRD bromodomain, BRDT testis-specific BRD protein, CBP CREB binding protein, CECR2 cat eye syndrome critical region protein 2, hGCN5 general control of amino acid synthesis protein 5, HRX/ALL histone-lysine N-methyltransferase HRX, MYND11 myeloid translocation protein 8, Nervy, and DEAF-1, domain-containing protein 11, NURF nucleosome-remodeling factor subunit, PCAF p300/ CREB-binding protein-associated factor, PHD plant homeodomain, SNF SWI/SNF remodeling complex protein, TAF1 transcription initiation factor TFIID subunit 1, TFIID transcription initiation factor, TIF transcription intermediate factor, TRI66 tripartite motif-containing protein 66, HOTTL tubulin-tyrosine ligase-like protein 3

The BRD group contains one or more structures determined by the RIKEN Structural Genomics/Proteomics Initiative or the Structural Genomics Consortium, for which no associated article is available.

五年级上册成语解释及近义词反义词和造句大全.doc

五年级上册成语解释及近义词反义词和造句大全囫囵吞枣；【解释】：囫囵：整个儿。把枣整个咽下去，不加咀嚼，不辨味道。比喻对事物不加分析考虑。【近义词】：不求甚解【反义词】融会贯穿[造句];学习不能囫囵吞枣而是要精益求精不求甚解；bùqiúshènjiě【解释】：甚：专门，极。只求明白个大概，不求完全了解。常指学习或研究不认真、不深入【近义词】：囫囵吞枣【反义词】：精益求精造句；1；在学习上，我们要理解透彻，不能不求甚解 2；学习科学文化知识要刻苦钻研，深入领会，不能粗枝大叶，不求甚解。千篇一律；【解释】：一千篇文章都一个样。指文章公式化。也比喻办事按一个格式，专门机械。【近义词】：千人一面、如出一辙【反义词】：千差万别、形形色色造句；学生旳作文千篇一律，专门少能有篇与众不同旳，这确实是平常旳练习太少了。倾盆大雨；qīngpéndàyǔ【解释】：雨大得象盆里旳水直往下倒。形容雨大势急。【近义词】：大雨如柱、大雨滂沱【反义词】：细雨霏霏牛毛细雨造句；3月旳天说变就变，瞬间下了一场倾盆大雨。今天下了一场倾盆大雨。坚决果断；áobùyóuyù：意思；做事果断，专门快拿定了主意，一点都不迟疑，形容态度坚决近义词；不假思索斩钉截铁反义词；犹豫不决造句；1看到小朋友落水，司马光坚决果断地搬起石头砸缸。2我坚决果断旳承诺了她旳要求。饥肠辘辘jīchánglùlù【近义词】：饥不择食【反义词】：丰衣足食造句；1我放学回家已是饥肠辘辘。2那个饥肠辘辘旳小孩差不多两天没吃饭了滚瓜烂熟gǔnguālànshóu〔shú)【解释】：象从瓜蔓上掉下来旳瓜那样熟。形容读书或背书流利纯熟。【近义词】：倒背如流【反义词】：半生半熟造句；1、这篇课文我们早已背得滚瓜烂熟了流光溢彩【liúguāngyìcǎi】解释；光影，满溢旳色彩，形容色彩明媚造句：国庆节，商场里装饰旳流光溢彩。津津有味；jīnjīnyǒuwèi解释：兴趣浓厚旳模样。指吃得专门有味道或谈得专门有兴趣。【近义词】：兴致勃勃有滋有味【反义词】：索然无味、枯燥无味造句；1今天旳晚餐真丰富，小明吃得津津有味。天长日久；tiānchángrìjiǔ【解释】：时刻长，生活久。【近义词】：天长地久【反义词】：稍纵即逝造句：小缺点假如不立即改掉, 天长日久就会变成坏适应如醉如痴rúzuìrúchī【解释】：形容神态失常，失去自制。【近义词】：如梦如醉【反义词】：恍然大悟造句；这么美妙旳音乐，我听得如醉如痴。浮想联翩【fúxiǎngliánpiān解释】：浮想：飘浮不定旳想象；联翩：鸟飞旳模样，比喻连续不断。指许许多多旳想象不断涌现出来。【近义词】：思绪万千造句；1他旳话让人浮想联翩。2:这幅画饱含诗情，使人浮想联翩，神游画外，得到美旳享受。悲欢离合bēihuānlíhé解释；欢乐、离散、聚会。泛指生活中经历旳各种境遇和由此产生旳各种心情【近义词】：酸甜苦辣、喜怒哀乐【反义词】：平淡无奇造句；1人一辈子即是悲欢离合,总要笑口常开,我们旳生活才阳光明媚. 牵肠挂肚qiānchángguàdù【解释】：牵：拉。形容十分惦念，放心不下造句；儿行千里母担忧，母亲总是那个为你牵肠挂肚旳人如饥似渴rújīsìkě：形容要求专门迫切，仿佛饿了急着要吃饭，渴了急着要喝水一样。造句；我如饥似渴地一口气读完这篇文章。他对知识旳如饥似渴旳态度造就了他今天旳成功。不言而喻bùyánéryù【解释】：喻：了解，明白。不用说话就能明白。形容道理专门明显。【近义词】：显而易见【反义词】：扑朔迷离造句；1珍惜时刻，好好学习，那个道理是不言而喻旳与众不同；yǔzhòngbùtóng【解释】：跟大伙不一样。〖近义词〗别出心裁〖反义词〗平淡无奇。造句； 1从他与众不同旳解题思路中，看出他专门聪慧。2他是个与众不同旳小孩

PEP六年级上册英语教案全册

Unit 1How can I get there? 第一课时一、教学内容 Part A Let's try & Let's talk 二、教学目标 1．能够听、说、读、写句子：“Where is the museum shop？”“It's near the door.”。 2．能够听、说、认读单词ask、sir和句型“Is there a…？”“I want to…”“What a great museum！”。三、教学重难点 1．学习句子“Where is the museum shop？”“It's near the door.”。 2．正确使用方位介词。四、教学准备单词卡、录音机、磁带。五、教学过程 Step 1 热身(Warming－up) Let's do Go to the bookstore.Buy some books. Go to the post office.Send a letter. Go to the hospital.See the doctor. Go to the cinema.See a film.

Go to the museum.See some robots. Step 2 新课呈现(Presentation) 1．学习Let's try (1)打开课本读一读Let's try中呈现的问题和选项。 (2)播放录音，让学生听完后勾出正确的选项。 (3)全班核对答案。 2．学习Let's talk (1)播放Let's talk的录音，学生带着问题听录音：Where is the museum shop？Where is the post office？听完录音后让学生回答这两个问题，教师板书：It's near the door.It's next to the museum.教师讲解：near表示“在附近”，next to表示“与……相邻”，它的范围比near小。最后让学生用near和next to来讲述学校周围的建筑物。 (2)讲解“A talking robot！What a great museum！”，让学生说说这两个感叹句的意思。 (3)再次播放录音，学生一边听一边跟读。 (4)分角色朗读课文。 Step 3 巩固与拓展(Consolidation and extension) 1．三人一组分角色练习Let's talk的对话，然后请一些同学到台前表演。 2．教学Part A：Talk about the places in your city/town/village.

The way常见用法

The way 的用法 Ⅰ常见用法： 1)the way+ that 2)the way + in which（最为正式的用法） 3)the way + 省略（最为自然的用法）举例：I like the way in which he talks. I like the way that he talks. I like the way he talks. Ⅱ习惯用法：在当代美国英语中，the way用作为副词的对格，“the way+ 从句”实际上相当于一个状语从句来修饰整个句子。 1)The way =as I am talking to you just the way I’d talk to my own child. He did not do it the way his friends did. Most fruits are naturally sweet and we can eat them just the way they are—all we have to do is to clean and peel them. 2）The way= according to the way/ judging from the way The way you answer the question, you are an excellent student. The way most people look at you, you’d think trash man is a monster. 3）The way =how/ how much No one can imagine the way he missed her. 4）The way =because

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悲惨的近义词反义词和造句导读：悲惨的近义词悲凉(注释:悲哀凄凉：～激越的琴声。) 悲惨的反义词幸福(注释:个人由于理想的实现或接近而引起的一种内心满足。追求幸福是人们的普遍愿望，但剥削阶级把个人幸福看得高于一切，并把个人幸福建立在被剥削阶级的痛苦之上。无产阶级则把争取广大人民的幸福和实现全人类的解放看作最大的幸福。认为幸福不仅包括物质生活，也包括精神生活;个人幸福依赖集体幸福，集体幸福高于个人幸福;幸福不仅在于享受，而主要在于劳动和创造。) 悲惨造句 1.一个人要发现卓有成效的真理，需要千百个人在失败的探索和悲惨的错误中毁掉自己的生命。 2.贝多芬的童年尽管如是悲惨，他对这个时代和消磨这时代的地方，永远保持着一种温柔而凄凉的回忆。 3.卖火柴的小女孩在大年夜里冻死了，那情景十分悲惨。 4.他相信，他们每个人背后都有一个悲惨的故事。 5.在那次悲惨的经历之后，我深信自己绝对不是那种可以离家很远的人。 6.在人生的海洋上，最痛快的事是独断独航，但最悲惨的却是回头无岸。 7.人生是艰苦的。对不甘于平庸凡俗的人那是一场无日无夜的斗

争，往往是悲惨的、没有光华的、没有幸福的，在孤独与静寂中展开的斗争。……他们只能依靠自己，可是有时连最强的人都不免于在苦难中蹉跎。罗曼·罗兰 8.伟大的心胸，应该表现出这样的气概用笑脸来迎接悲惨的厄运，用百倍的勇气来应付开始的不幸。鲁迅人在逆境里比在在顺境里更能坚强不屈。遇厄运时比交好运时容易保全身心。 9.要抓紧时间赶快生活，因为一场莫名其妙的疾病，或者一个意外的悲惨事件，都会使生命中断。奥斯特洛夫斯基。 10.在我一生中最悲惨的一个时期，我曾经有过那类的想法：去年夏天在我回到这儿附近的地方时，这想法还缠着我;可是只有她自己的亲自说明才能使我再接受这可怕的想法。 11.他们说一个悲惨的故事是悲剧，但一千个这样的故事就只是一个统计了。 12.不要向诱惑屈服，而浪费时间去阅读别人悲惨的详细新闻。 13.那起悲惨的事件深深地铭刻在我的记忆中。 14.伟大的心胸，应该用笑脸来迎接悲惨的厄运，用百倍的勇气来应付一切的不幸。 15.一个人要发现卓有成效的真理，需要千百万个人在失败的探索和悲惨的错误中毁掉自己的生命。门捷列夫 16.生活需要爱，没有爱，那些受灾的人们生活将永远悲惨;生活需要爱，爱就像调味料，使生活这道菜充满滋味;生活需要爱，爱让生活永远充满光明。

人教版六年级上册英语知识点总结

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The way的用法及其含义（二）二、the way在句中的语法作用 the way在句中可以作主语、宾语或表语： 1.作主语 The way you are doing it is completely crazy.你这个干法简直发疯。 The way she puts on that accent really irritates me. 她故意操那种口音的样子实在令我恼火。The way she behaved towards him was utterly ruthless. 她对待他真是无情至极。 Words are important, but the way a person stands, folds his or her arms or moves his or her hands can also give us information about his or her feelings. 言语固然重要,但人的站姿,抱臂的方式和手势也回告诉我们他(她)的情感。 2.作宾语 I hate the way she stared at me.我讨厌她盯我看的样子。 We like the way that her hair hangs down.我们喜欢她的头发笔直地垂下来。 You could tell she was foreign by the way she was dressed. 从她的穿著就可以看出她是外国人。 She could not hide her amusement at the way he was dancing. 她见他跳舞的姿势，忍俊不禁。 3.作表语 This is the way the accident happened.这就是事故如何发生的。 Believe it or not, that's the way it is. 信不信由你, 反正事情就是这样。 That's the way I look at it, too. 我也是这么想。 That was the way minority nationalities were treated in old China. 那就是少数民族在旧中

PEP人教版小学六年级上册英语期末分类专项复习试题及答案(全套)

分类专项复习卷（一）听力建议时间：40分钟满分：100分一、听录音，选择你所听到的内容，将其序号填入题前括号里。（5分）( ) 1. A. afraid B. amazing C. attention ( ) 2. A. can’t go to school B. count to ten C. don’t be late ( ) 3. A. a TV reporter B. a sports reporter C. a PE teacher ( ) 4. A. I want to buy a postcard. B. I want to send the postcard. C. I want to go to the post office. ( ) 5. A. It’s next to the restaurant B. It’s near the museum shop. C. It’s behind the supermarket. 二、听录音，选择与你所听到的内容相符的图片，将其序号填入题前括号里。（5分） ( ) 1. A. B. C. ( ) 2. A. B. C. ( ) 3. A. B. C. ( ) 4. A. B. C. ( ) 5. A. B. C. 三、听录音，用数字给下列图片排序。（6分）

（）（）（） ( ) ( ) ( ) 四、听录音，判断下列句子与你所听到的内容是否相符，相符的写“√”，不相符的写“×”。（5分） ( ) l. Mike should see a doctor in the morning. ( ) 2. Amy’s father works at sea. ( ) 3. Mike’s brother is a postman. ( ) 4. Peter likes doing kung fu and swimming. ( ) 5. We are going to Beijing next Tuesday. 五、听录音，判断下列图片与你所听到的内容是否相符，相符的打“√”，不相符的打“×”。（6分） 1. ( ) 2. ( ) 3. ( ) 4. ( ) 5. ( ) 6. ( ) 六、听录音，选择相应的答语，将其序号填入题前括号里。（7分） ( ) 1. A. He’s over there. B. Thank you. C. Great! ( ) 2. A. Here you are. B. Sure. C. Thanks. ( ) 3. A. Please turn left. B. It’s near the door.

新版pep六年级上册英语-各单元知识点总结

Unit 1 How can I get there? 一：重点单词和短语 Science科学, museum博物馆, post office, bookstore, cinema, hospital ，tasty, buy, London Eye伦敦银, stomach胃,crossing十字路口, turn left, turn right, go straight=walk straight直走.next to紧挨着/与。。。相邻, far from(离。。。远), near在。。。附近,behind（在。。。后面）, in front of（在。。。前面）, between…and…（在。。。和。。。之间）二：按要求写单词： hot(反义词)cold , cool(反义词)warm，too（同音词）to/two can not(缩写)can’t right(反义词)left/wrong buy(同音词)by/bye sea(同音词)see first（基数词）one four(序数词)fourth did (原形)do /does three(序数词)third give(过去式)gave 三：重点句型分析 1. Where is the museum shop? 此问句是由特殊疑问词where 引导的一个特殊疑问句，where意为“在哪里，到哪里”，用来询问地点，放在句子的开头。询问“某人或某物在哪里”的基本句型是：“ Where +is/are+ 主语？”，where is 后接名词或代词的单数形式，where are 后接名词或代词的复数形式。表示地点的词：museum博物馆, post office邮局, bookstore书店, cinema电影院, hospital医院restaurant餐馆bank银行bus stop 公交车站lake湖library图书馆zoo动物园school学校park公园garden花园hotel旅馆 2. It’s nea r the door. 此句中near是表示位置的介词，意为“旁边，附近” ，其同义句是：It’s next to the door.它在门的旁边。表示位置的短语：next to the bookstore挨着书店near the hospital在医院附近near the post office在邮局附近over there 在那边on Dongfang Street在东方大街上in front of the school在学校前面 3. How can we get there? 此句用来询问“怎样去某地”，后面直接跟地点。回答时，可以用“ Turn left, turn right, go straight.”等句来回答。同义句：1.Can you tell me the way to+地点？ 2.Where is the +地点？ 3.Which is the way to +地点 4. Turn left at the bookstore. Then turn right at the hospital. 此句是指路的句型。常用到的句型有：turn left, 向左转turn right, 向右转go straight直着走。同时表示在某处的介词用at. 5.Is the Thames far from here? No, it isn’t. 此句是个be动词开头的一般疑问句，其回答要用Yes或No. 句中的far from意为“离……远”。反义词组为next to.

(完整版)the的用法

定冠词the的用法：定冠词the与指示代词this ,that同源,有“那(这)个”的意思,但较弱,可以和一个名词连用,来表示某个或某些特定的人或东西. (1)特指双方都明白的人或物 Take the medicine.把药吃了. (2)上文提到过的人或事 He bought a house.他买了幢房子. I've been to the house.我去过那幢房子. (3)指世界上独一无二的事物 the sun ,the sky ,the moon, the earth (4)单数名词连用表示一类事物 the dollar 美元 the fox 狐狸或与形容词或分词连用,表示一类人 the rich 富人 the living 生者 (5)用在序数词和形容词最高级,及形容词等前面 Where do you live?你住在哪? I live on the second floor.我住在二楼. That's the very thing I've been looking for.那正是我要找的东西. (6)与复数名词连用,指整个群体 They are the teachers of this school.(指全体教师) They are teachers of this school.(指部分教师) (7)表示所有,相当于物主代词,用在表示身体部位的名词前 She caught me by the arm.她抓住了我的手臂. (8)用在某些有普通名词构成的国家名称,机关团体,阶级等专有名词前 the People's Republic of China 中华人民共和国 the United States 美国 (9)用在表示乐器的名词前 She plays the piano.她会弹钢琴. (10)用在姓氏的复数名词之前,表示一家人 the Greens 格林一家人(或格林夫妇) (11)用在惯用语中 in the day, in the morning... the day before yesterday, the next morning... in the sky... in the dark... in the end... on the whole, by the way...

人教版小学六年级上册英语时态专项习题

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“the way+从句”结构的意义及用法

“tｈｅwａｙ+从句”结构的意义及用法首先让我们来看下面这个句子: Ｒead the foｌloｗｉnｇpassagｅａnd talkａbout ｉt wi ｔh your classmaｔes．Try tｏｔeｌl whaｔyｏu thiｎk ｏf Tom aｎd ｏｆｔhe ｗay the chiｌｄrenｔrｅated ｈim. 在这个句子中，ｔhe waｙ是先行词,后面是省略了关系副词that或in whｉch的定语从句。下面我们将叙述“the ｗaｙ+从句”结构的用法。 1.tｈe wａy之后，引导定语从句的关系词是tｈat而不是hoｗ,因此，<<现代英语惯用法词典＞＞中所给出的下面两个句子是错误的：Ｔhｉs is ｔｈeｗayｈowｉtｈａppened. This is the way how he ａlwａｙs treats me. 2．在正式语体中,thaｔ可被in which所代替;在非正式语体中，ｔhat则往往省略。由此我们得到theｗay后接定语从句时的三种模式：1) tｈe ｗaｙ＋ｔhａt-从句２）the way +ｉn whiｃh－从句3) the ｗay +从句例如：Ｔｈe way(in whiｃh ，thａt) ｔhｅｓｅｃomｒade ｓloｏｋａｔｐrobｌems is wrong．这些同志看问题的方法

不对。Ｔｈｅｗａy(that ,ｉn ｗhiｃh)yoｕ’ｒe doinｇit is comple ｔeｌy crａzy.你这么个干法,简直发疯。 Wｅａdmiｒｅd him for thｅｗay ｉｎｗhｉch he fａｃeｓdiｆficultieｓ． Waｌlａｃe ａｎd Ｄarwiｎｇreed ｏn the way ｉｎwhi ｃh ｄｉfｆｅrｅnt forms ｏf life had ｂegｕn.华莱士和达尔文对不同类型的生物是如何起源的持相同的观点。 Thｉs is ｔｈe ｗaｙ（tｈａｔ) hｅdｉd it. I lｉkeｄｔhe waｙ(ｔhat) ｓｈeｏｒganized ｔhe ｍeetｉng． 3.theｗay(tｈat)有时可以与hｏw(作“如何”解）通用。例如： That’s tｈe ｗaｙ(tｈaｔ) shｅspoke. = Tｈat’s how shｅspoke.

人教版六年级上册英语语音专项练习题

1 一、找出划线部分读音与其他三个不同的单词。（）1.A.how B.know C.yellow D.window （）2. A.apple B.cat C.many D.mango （）3. A.not B.doctor C.kilo D.orange （）4. A.pears B.bananas C.apples D.grapes （）5. A.boxes B.peaches C.buses D.apples （）6. A.these B.thirsty C.those D.they 一、选出划线部分读音与所给单词划线部分读音相同的一项。（）1.baseball A.table B.father C.banana （）2. brother A.nose B.doctor C.son （）3. which A.knife B.with C.white （）4. this A.mouth B.three C.with （）5. room A.too B.book C.good （）6. ear A.pear B.bear C.hear 二、找出划线部分读音与其他三个不相同的单词。 ( )1.A.hurry B.student C.puppet D.bus ( )2. A.that B.think C.mouth D.thank ( )3. A.guess B.she C.egg D.watermelon ( )4. A.right B.climb C.this D.pineapple ( )5. A.mother B.today https://www.wendangku.net/doc/963287393.html,e D.some 三、找出与所给单词划线部分读音相同的单词。 1.( )father A.mouth B.brother 2. ( )nose A.close B.seven 3. ( )cake https://www.wendangku.net/doc/963287393.html,te B.father 4. ( )sister A.bike B.is 5. ( )boy A.climb B.brother 6. ( )mother A.sister B.her 四、判断下列划线部分读音是否相同， ( )1.driver write ( )driver teacher ( )2.farmer her ( )knife big ( )3.cook good ( )drink dress ( )4.tree trousers ( )look school ( )5.their hair ( )where here ( )6.that mouth ( )they those 五、将下列单词按th 的两种发音分类。 that mouth this three think thin thank thirsty those there these they [that] th [ ] mouth 六、单词辨音，用“√”或“×”表示。 student ( ) bus ( ) bananas pear grapes ( ) ear ( ) teacher nose worker ( ) orange ( ) tree ( ) dress ( ) 八．判断下列划线部分读音是否相同，用“√”或“×”表示。 1.hair airport ( ) 2.ship shop( ) 3.where who ( ) 4.good school ( ) 5.minibus student( ) 6.station library( ) 九．找出划线部分读音与其他不相同的单词。 ( )1.A.move B.noodle C.who D.coffee ()2. A.sweets B.friends C.cats D.biscuits ( )3. A.apple B.water C.at D.bag ( )4. A.juice B.cup C.bus D.much ( )5. https://www.wendangku.net/doc/963287393.html,k B.it C.kite D.his ( )6. A.classroom B.bedroom C.room D.bathroom 十一、找出与所给单词划线部分读音相同的单词。 1.music A.bus B.student C.cup D.buy 2.chocolate A.goB.open C.too D.office 3.teacher A.school https://www.wendangku.net/doc/963287393.html,e C.lunch D.cake 4.bookcase https://www.wendangku.net/doc/963287393.html,te B.cap C.apple D.snack 5.desk A.grape B.bed C.she D.he 6.kilo A.library B.like C.tiger D.hospital 7.oranges A.booksB.cats C.teachers D.maps 8.chair A.pear B.here C.ear D.dear 十二、判断下列划线部分读音是否相同，用“√”或“×”表示。 1.bread egg ( ) 2.plate snack ( ) 3.where whose ( ) 4.try right ( ) 5.bowl how ( ) 6.chopstick school( )

知己的近义词反义词及知己的造句

知己的近义词反义词及知己的造句本文是关于知己的近义词反义词及知己的造句，感谢您的阅读！知己的近义词反义词及知己的造句知己基本解释：顾名思义是了解、理解、赏识自己的人，如"知己知彼，百战不殆";更常指懂你自己的挚友或密友，它是一生难求的朋友，友情的最高境界。正所谓:"士为知己者死"。 1.谓了解、理解、赏识、懂自己。 2.彼此相知而情谊深切的人。【知己近义词】亲信，好友，密友，心腹，挚友，深交，相知，知交，知友，知心，知音，石友，老友，至友【知己反义词】仇人敌人陌路【知己造句】 1、我们想要被人爱、想拥有知己、想历经欢乐、想要安全感。 2、朋友本应是我们的亲密知己和支持者，但对于大多数人来说，有一些朋友比起帮助我们，更多的却是阻碍。 3、那么，为什么你就认为，随着年龄的增长，比起女人来男人们的知己和丰富的人际关系更少，因此一般容易更孤独呢？ 4、他成了我的朋友、我的知己、我的顾问。 5、无论在我当州长还是总统的时候，布鲁斯都是我的密友、顾问和知己。他这样的朋友人人需要，也是所有总统必须拥有的。

6、波兰斯基有着一段声名卓著的电影生涯，也是几乎所有电影界重要人物们的挚友和同事，他们是知己，是亲密的伙伴。 7、搜索引擎变成了可以帮追我们的忏悔室，知己，信得过的朋友。 8、这样看来，奥巴马国家安全团队中最具影响力的当属盖茨了――但他却是共和党人，他不会就五角大楼以外问题发表看法或成为总统知己。 9、我们的关系在二十年前就已经和平的结束了，但在网上，我又一次成为了他精神层面上的评论家，拉拉队，以及红颜知己。 10、这位“知己”，作为拍摄者，站在距离电视屏幕几英尺的地方对比着自己年轻版的形象。 11、父亲与儿子相互被形容为对方的政治扩音筒、知己和后援。 12、这对夫妻几乎没有什么至交或知己依然在世，而他们在后纳粹时期的德国也不可能会说出实话的。 13、她把我当作知己，于是，我便将她和情人之间的争吵了解得一清二楚。 14、有一种友谊不低于爱情；关系不属于暖昧；倾诉一直推心置腹；结局总是难成眷属；这就是知己！ 15、把你的治疗师当做是可以分享一切心事的知己。 16、莉莉安对我敞开心胸，我成了她的知己。 17、据盖洛普民意调查显示，在那些自我认同的保守党人中，尽管布什仍维持72%支持率，但他在共和党领导层中似乎很少有几位知

PEP小学英语六年级上册各单元知识点复习资料

六年级上复习资料 Unit1 How Do You Go There? (你怎样去那里？) 重点单词： on foot= walk走路by bike骑自行车by bus坐公车by train坐火车by plane坐飞机by ship坐轮船by subway坐地铁near近的far远的usually通常sometimes有时候easy简单的the fifth floor第五层楼traffic lights交通灯traffic rules交通规则stop停止wait等待get to到达same相同的mean意思是driver司机right 右边left左边must必须know知道重点句子： 1. How do you go to school? 你是怎样去上学的？ 2. I go to school by bus.我是坐公交车去上学的。 3. Usually I go to school on foot. 我通常走路去上学。 4. Sometimes I go by bike. 有时候我骑自行车去。、 5. My home is near/ far. 我的家是近的。/ 远的。 6. Look at the traffic lights, remember the traffic rules. 看着交通灯，记住交通规则。 7. Stop at a red light. Wait at a yellow light. Go at a green light. 红灯停。黄灯等一等。绿灯行。 8. Red means stop, yellow means wait, green means go. 红色的意思是停止，黄色的意思是等待，绿色的意思是通行。 9. How can I get to the park? 我该怎样到达公园呢？ 10. You can go by the No. 15 bus. 你可以坐15路公交车去。重点知识： 1.坐某种交通工具用by，例如：by bike, by train。而走路用“on”例如on foot. 2.国家名字，地方名字第一个字母要大些：例如：Canada加拿大, China中国, America美国，England英国，Australia澳大利亚 3.国家名缩写前面加the，缩写字母都要大写。例如：the USA=the US美国，the UK英国，the CAN加拿大，the PRC中国。 4.频度副词是表示做的次数多少的词语。从多到少依次排列为：always总是，usually通常，often经常，sometimes有时候，never从不。频度副词可以放在句首，也可以放在人称后面。例如：Usually I go to school by bus. = I usually go to school by bus. 5.near近的，far远的。这两个词是一对反义词。注意：not near= far, not far = near. 6.时间前面用at. 例如：在三点钟：at 3 o’ clock. 一段时间前面用for 7.表达第几层楼的时候我们要用序数词，前面还要有the。例如：第一、二、三、四、五层楼分别是：the first floor. the second floor. the third floor. the fourth floor. the fifth floor. 8.交通灯traffic lights，交通规则：traffic rules。这两个词后面都一定要加s, 绝对不能少。因为交通灯有红黄绿三盏，一定是复数，交通规则不可能只有一条，所以都一定要加s，考试的时候千万别忘了加s哦！ 9.大部分的国家都是靠右行驶的：drivers drive on the right side of the road. 记住England and Australia, drivers drive on the left side of the road.英国和澳大利亚，司机是靠左行驶的。

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