4z93

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(Difference between revisions)

Revision as of 12:11, 12 April 2017

BRD4 bromodomain 2 in complex with gamma-carboline-containing compound, number 18.

Structural highlights

4z93 is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
NonStd Res:
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

Small-molecule inhibitors of bromodomain and extra terminal proteins (BET), including BRD2, BRD3, and BRD4 proteins have therapeutic potential for the treatment of human cancers and other diseases and conditions. In this paper, we report the design, synthesis, and evaluation of gamma-carboline-containing compounds as a new class of small-molecule BET inhibitors. The most potent inhibitor (compound 18, RX-37) obtained from this study binds to BET bromodomain proteins (BRD2, BRD3, and BRD4) with Ki values of 3.2-24.7 nM and demonstrates high selectivity over other non-BET bromodomain-containing proteins. Compound 18 potently and selectively inhibits cell growth in human acute leukemia cell lines harboring the rearranged mixed lineage leukemia 1 gene. We have determined a cocrystal structure of 18 in complex with BRD4 BD2 at 1.4 A resolution, which provides a solid structural basis for the compound's high binding affinity and for its further structure-based optimization. Compound 18 represents a promising lead compound for the development of a new class of therapeutics for the treatment of human cancer and other conditions.

Structure-Based Design of gamma-Carboline Analogues as Potent and Specific BET Bromodomain Inhibitors.,Ran X, Zhao Y, Liu L, Bai L, Yang CY, Zhou B, Meagher JL, Chinnaswamy K, Stuckey JA, Wang S J Med Chem. 2015 Jun 25;58(12):4927-39. doi: 10.1021/acs.jmedchem.5b00613. Epub, 2015 Jun 16. PMID:26080064^[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
↑ Ran X, Zhao Y, Liu L, Bai L, Yang CY, Zhou B, Meagher JL, Chinnaswamy K, Stuckey JA, Wang S. Structure-Based Design of gamma-Carboline Analogues as Potent and Specific BET Bromodomain Inhibitors. J Med Chem. 2015 Jun 25;58(12):4927-39. doi: 10.1021/acs.jmedchem.5b00613. Epub, 2015 Jun 16. PMID:26080064 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b00613

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/4z93"

Categories: Meagher, J L | Stuckey, J A | Bromodomain | Transcription

@@ Line 1: / Line 1: @@
 ==BRD4 bromodomain 2 in complex with gamma-carboline-containing compound, number 18.==
 <StructureSection load='4z93' size='340' side='right' caption='[[4z93]], [[Resolution|resolution]] 1.27&Aring;' scene=''>
@@ Line 5: / Line 6: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4LD:1-(3-CYCLOPROPYL-5-METHYL-1H-PYRAZOL-4-YL)-7-(3,5-DIMETHYL-1,2-OXAZOL-4-YL)-8-METHOXY-5H-PYRIDO[4,3-B]INDOLE'>4LD</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
 <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</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=4z93 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4z93 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4z93 RCSB], [http://www.ebi.ac.uk/pdbsum/4z93 PDBsum]</span></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=4z93 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4z93 OCA], [http://pdbe.org/4z93 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4z93 RCSB], [http://www.ebi.ac.uk/pdbsum/4z93 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4z93 ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 19: / Line 20: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4z93" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Bromodomain-containing protein|Bromodomain-containing protein]]
 == References ==
 <references/>

4z93

From Proteopedia

Revision as of 12:11, 12 April 2017

BRD4 bromodomain 2 in complex with gamma-carboline-containing compound, number 18.

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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