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6cd5

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Revision as of 08:17, 21 February 2019

Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor XMD17-26

Structural highlights

6cd5 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Gene:	BRD4, HUNK1 (HUMAN)
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

Bromodomains have been pursued intensively over the past several years as emerging targets for the devel-opment of anti-cancer and anti-inflammatory agents. It has recently been shown that some kinase inhibitors are able to potently inhibit the bromodomains of BRD4. The clinical activities of PLK inhibitor BI-2536 and JAK2-FLT3 inhibitor TG101348 have been attributed to this unexpected poly-pharmacology, indicating that dual-kinase/bromodomain activity may be advantageous in a therapeutic context. However, for target validation and biological investigation, a more selec-tive target profile is desired. Here we report that benzo[e]pyrimido-[5,4-b]diazepine-6(11H)-ones, versatile ATP-site di-rected kinase pharmacophores utilized in the development of inhibitors of multiple kinases including a number of previ-ously reported kinase chemical probes, are also capable of exhibiting potent BRD4-dependent pharmacology. Using a dual kinase-bromodomain inhibitor of the kinase domains of ERK5 and LRRK2, and the bromodomain of BRD4 as a case study, we define the structure-activity relationships required to achieve dual kinase/BRD4 activity as well as how to di-rect selectivity towards inhibition of either ERK5 or BRD4. This effort resulted in identification of one of the first report-ed kinase-selective chemical probes for ERK5 (JWG-071), a BET selective inhibitor with 1 muM BRD4 IC50 (JWG-115), and additional inhibitors with rationally designed polypharmacology (JWG-047, JWG-069). Co-crystallography of seven representative inhibitors with the first bromodomain of BRD4 demonstrate that distinct atropisomeric conformers rec-ognize the kinase ATP-site and the BRD4 acetyl lysine binding site, conformational preferences supported by rigid dock-ing studies.

Structural and atropisomeric factors governing the selectivity of pyrimido-benzodiazipinones as inhibitors of kinases and bromodomains.,Wang J, Erazo T, Ferguson FM, Buckley DL, Gomez N, Munoz-Guardiola P, Dieguez-Martinez N, Deng X, Hao M, Massefski W, Fedorov O, Offei-Addo NK, Park PM, Dai L, DiBona A, Becht K, Kim ND, McKeown MR, Roberts JM, Zhang J, Sim T, Alessi DR, Bradner JE, Lizcano JM, Blacklow SC, Qi J, Xu X, Gray NS ACS Chem Biol. 2018 Aug 13. doi: 10.1021/acschembio.7b00638. PMID:30102854^[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
↑ Wang J, Erazo T, Ferguson FM, Buckley DL, Gomez N, Munoz-Guardiola P, Dieguez-Martinez N, Deng X, Hao M, Massefski W, Fedorov O, Offei-Addo NK, Park PM, Dai L, DiBona A, Becht K, Kim ND, McKeown MR, Roberts JM, Zhang J, Sim T, Alessi DR, Bradner JE, Lizcano JM, Blacklow SC, Qi J, Xu X, Gray NS. Structural and atropisomeric factors governing the selectivity of pyrimido-benzodiazipinones as inhibitors of kinases and bromodomains. ACS Chem Biol. 2018 Aug 13. doi: 10.1021/acschembio.7b00638. PMID:30102854 doi:http://dx.doi.org/10.1021/acschembio.7b00638

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6cd5"

@@ Line 3: / Line 3: @@
 <StructureSection load='6cd5' size='340' side='right' caption='[[6cd5]], [[Resolution|resolution]] 1.58&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6cd5]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CD5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CD5 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6cd5]] is a 1 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=6CD5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CD5 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene>, <scene name='pdbligand=R4L:11-CYCLOPENTYL-2-[[2-METHOXY-4-[4-(4-METHYLPIPERAZIN-1-YL)PIPERIDIN-1-YL]CARBONYL-PHENYL]AMINO]-5-METHYL-PYRIMIDO[4,5-B][1,4]BENZODIAZEPIN-6-ONE'>R4L</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BRD4, HUNK1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6cd5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cd5 OCA], [http://pdbe.org/6cd5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6cd5 RCSB], [http://www.ebi.ac.uk/pdbsum/6cd5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6cd5 ProSAT]</span></td></tr>
 </table>
@@ Line 24: / Line 25: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Blacklow, S C]]
 [[Category: Xu, X]]

6cd5

From Proteopedia

Revision as of 08:17, 21 February 2019

Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor XMD17-26

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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