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5ad2

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Bivalent binding to BET bromodomains

Structural highlights

5ad2 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.01Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

BRD4_HUMAN Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein.^[1] ^[2]

Function

BRD4_HUMAN Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).

Publication Abstract from PubMed

Proteins of the bromodomain and extraterminal (BET) family, in particular bromodomain-containing protein 4 (BRD4), are of great interest as biological targets. BET proteins contain two separate bromodomains, and existing inhibitors bind to them monovalently. Here we describe the discovery and characterization of probe compound biBET, capable of engaging both bromodomains simultaneously in a bivalent, in cis binding mode. The evidence provided here was obtained in a variety of biophysical and cellular experiments. The bivalent binding results in very high cellular potency for BRD4 binding and pharmacological responses such as disruption of BRD4-mediator complex subunit 1 foci with an EC50 of 100 pM. These compounds will be of considerable utility as BET/BRD4 chemical probes. This work illustrates a novel concept in ligand design-simultaneous targeting of two separate domains with a drug-like small molecule-providing precedent for a potentially more effective paradigm for developing ligands for other multi-domain proteins.

Potent and selective bivalent inhibitors of BET bromodomains.,Waring MJ, Chen H, Rabow AA, Walker G, Bobby R, Boiko S, Bradbury RH, Callis R, Clark E, Dale I, Daniels DL, Dulak A, Flavell L, Holdgate G, Jowitt TA, Kikhney A, McAlister M, Mendez J, Ogg D, Patel J, Petteruti P, Robb GR, Robers MB, Saif S, Stratton N, Svergun DI, Wang W, Whittaker D, Wilson DM, Yao Y Nat Chem Biol. 2016 Dec;12(12):1097-1104. doi: 10.1038/nchembio.2210. Epub 2016, Oct 24. PMID:27775716^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR, Fletcher JA. BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. Cancer Res. 2003 Jan 15;63(2):304-7. PMID:12543779
↑ French CA, Miyoshi I, Aster JC, Kubonishi I, Kroll TG, Dal Cin P, Vargas SO, Perez-Atayde AR, Fletcher JA. BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19). Am J Pathol. 2001 Dec;159(6):1987-92. PMID:11733348 doi:10.1016/S0002-9440(10)63049-0
↑ Waring MJ, Chen H, Rabow AA, Walker G, Bobby R, Boiko S, Bradbury RH, Callis R, Clark E, Dale I, Daniels DL, Dulak A, Flavell L, Holdgate G, Jowitt TA, Kikhney A, McAlister M, Mendez J, Ogg D, Patel J, Petteruti P, Robb GR, Robers MB, Saif S, Stratton N, Svergun DI, Wang W, Whittaker D, Wilson DM, Yao Y. Potent and selective bivalent inhibitors of BET bromodomains. Nat Chem Biol. 2016 Dec;12(12):1097-1104. doi: 10.1038/nchembio.2210. Epub 2016, Oct 24. PMID:27775716 doi:http://dx.doi.org/10.1038/nchembio.2210

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5ad2"

@@ Line 3: / Line 3: @@
 <StructureSection load='5ad2' size='340' side='right'caption='[[5ad2]], [[Resolution|resolution]] 2.01&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5ad2]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5AD2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5AD2 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5ad2]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5AD2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5AD2 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ETU:(3R)-4-(2-{4-[1-(3-CHLORO[1,2,4]TRIAZOLO[4,3-B]PYRIDAZIN-6-YL)-4-PIPERIDINYL]PHENOXY}ETHYL)-1,3-DIMETHYL-2-PIPERAZINONE'>ETU</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.01&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5ad3|5ad3]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ETU:(3R)-4-(2-{4-[1-(3-CHLORO[1,2,4]TRIAZOLO[4,3-B]PYRIDAZIN-6-YL)-4-PIPERIDINYL]PHENOXY}ETHYL)-1,3-DIMETHYL-2-PIPERAZINONE'>ETU</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ad2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ad2 OCA], [http://pdbe.org/5ad2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ad2 RCSB], [http://www.ebi.ac.uk/pdbsum/5ad2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ad2 ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5ad2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ad2 OCA], [https://pdbe.org/5ad2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ad2 RCSB], [https://www.ebi.ac.uk/pdbsum/5ad2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ad2 ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein.<ref>PMID:12543779</ref> <ref>PMID:11733348</ref>
+[https://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN] Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein.<ref>PMID:12543779</ref> <ref>PMID:11733348</ref>
 == Function ==
-[[http://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).
+[https://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 28: / Line 28: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Bobby, R]]
+[[Category: Bobby R]]
-[[Category: Boiko, S]]
+[[Category: Boiko S]]
-[[Category: Bradbury, R H]]
+[[Category: Bradbury RH]]
-[[Category: Callis, R]]
+[[Category: Callis R]]
-[[Category: Chen, H]]
+[[Category: Chen H]]
-[[Category: Dale, I]]
+[[Category: Dale I]]
-[[Category: Daniels, D]]
+[[Category: Daniels D]]
-[[Category: Flavell, L]]
+[[Category: Flavell L]]
-[[Category: Holdgate, G]]
+[[Category: Holdgate G]]
-[[Category: Jowitt, T A]]
+[[Category: Jowitt TA]]
-[[Category: Kikhney, A]]
+[[Category: Kikhney A]]
-[[Category: McAlister, M]]
+[[Category: McAlister M]]
-[[Category: Ogg, D]]
+[[Category: Ogg D]]
-[[Category: Patel, J]]
+[[Category: Patel J]]
-[[Category: Petteruti, P]]
+[[Category: Petteruti P]]
-[[Category: Rabow, A A]]
+[[Category: Rabow AA]]
-[[Category: Robb, G R]]
+[[Category: Robb GR]]
-[[Category: Robers, M]]
+[[Category: Robers M]]
-[[Category: Stratton, N]]
+[[Category: Stratton N]]
-[[Category: Svergun, D I]]
+[[Category: Svergun DI]]
-[[Category: Walker, G]]
+[[Category: Walker G]]
-[[Category: Wang, W]]
+[[Category: Wang W]]
-[[Category: Waring, M J]]
+[[Category: Waring MJ]]
-[[Category: Whittaker, D]]
+[[Category: Whittaker D]]
-[[Category: Transcription]]

5ad2

From Proteopedia

Current revision

Bivalent binding to BET bromodomains

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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