5wmg

From Proteopedia

(Difference between revisions)

Revision as of 09:40, 13 February 2019

N-terminal bromodomain of BRD4 in complex with OTX-015

Structural highlights

5wmg 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

Bromodomain and extra-terminal (BET) family proteins are key regulators of gene expression in cancer. Herein, we utilize BRD4 profiling to identify critical pathways involved in pathogenesis of chronic lymphocytic leukemia (CLL). BRD4 is overexpressed in CLL and is enriched proximal to genes upregulated or de novo expressed in CLL with known functions in disease pathogenesis and progression. These genes, including key members of the B-cell receptor (BCR) signaling pathway, provide a rationale for this therapeutic approach to identify new targets in alternative types of cancer. Additionally, we describe PLX51107, a structurally distinct BET inhibitor with novel in vitro and in vivo pharmacologic properties that emulates or exceeds the efficacy of BCR signaling agents in preclinical models of CLL. Herein, the discovery of the involvement of BRD4 in the core CLL transcriptional program provides a compelling rationale for clinical investigation of PLX51107 as epigenetic therapy in CLL and application of BRD4 profiling in other cancers.Significance: To date, functional studies of BRD4 in CLL are lacking. Through integrated genomic, functional, and pharmacologic analyses, we uncover the existence of BRD4-regulated core CLL transcriptional programs and present preclinical proof-of-concept studies validating BET inhibition as an epigenetic approach to target BCR signaling in CLL. Cancer Discov; 8(4); 458-77. (c)2018 AACR.This article is highlighted in the In This Issue feature, p. 371.

BRD4 Profiling Identifies Critical Chronic Lymphocytic Leukemia Oncogenic Circuits and Reveals Sensitivity to PLX51107, a Novel Structurally Distinct BET Inhibitor.,Ozer HG, El-Gamal D, Powell B, Hing ZA, Blachly JS, Harrington B, Mitchell S, Grieselhuber NR, Williams K, Lai TH, Alinari L, Baiocchi RA, Brinton L, Baskin E, Cannon M, Beaver L, Goettl VM, Lucas DM, Woyach JA, Sampath D, Lehman AM, Yu L, Zhang J, Ma Y, Zhang Y, Spevak W, Shi S, Severson P, Shellooe R, Carias H, Tsang G, Dong K, Ewing T, Marimuthu A, Tantoy C, Walters J, Sanftner L, Rezaei H, Nespi M, Matusow B, Habets G, Ibrahim P, Zhang C, Mathe EA, Bollag G, Byrd JC, Lapalombella R Cancer Discov. 2018 Apr;8(4):458-477. doi: 10.1158/2159-8290.CD-17-0902. Epub, 2018 Jan 31. PMID:29386193^[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
↑ Ozer HG, El-Gamal D, Powell B, Hing ZA, Blachly JS, Harrington B, Mitchell S, Grieselhuber NR, Williams K, Lai TH, Alinari L, Baiocchi RA, Brinton L, Baskin E, Cannon M, Beaver L, Goettl VM, Lucas DM, Woyach JA, Sampath D, Lehman AM, Yu L, Zhang J, Ma Y, Zhang Y, Spevak W, Shi S, Severson P, Shellooe R, Carias H, Tsang G, Dong K, Ewing T, Marimuthu A, Tantoy C, Walters J, Sanftner L, Rezaei H, Nespi M, Matusow B, Habets G, Ibrahim P, Zhang C, Mathe EA, Bollag G, Byrd JC, Lapalombella R. BRD4 Profiling Identifies Critical Chronic Lymphocytic Leukemia Oncogenic Circuits and Reveals Sensitivity to PLX51107, a Novel Structurally Distinct BET Inhibitor. Cancer Discov. 2018 Apr;8(4):458-477. doi: 10.1158/2159-8290.CD-17-0902. Epub, 2018 Jan 31. PMID:29386193 doi:http://dx.doi.org/10.1158/2159-8290.CD-17-0902

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/5wmg"

@@ Line 3: / Line 3: @@
 <StructureSection load='5wmg' size='340' side='right' caption='[[5wmg]], [[Resolution|resolution]] 1.19&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5wmg]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WMG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WMG FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5wmg]] 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=5WMG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WMG FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6JF:4-{6-(3,5-dimethyl-1,2-oxazol-4-yl)-1-[(1S)-1-(pyridin-2-yl)ethyl]-1H-pyrrolo[3,2-b]pyridin-3-yl}benzoic+acid'>6JF</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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=5wmg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wmg OCA], [http://pdbe.org/5wmg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wmg RCSB], [http://www.ebi.ac.uk/pdbsum/5wmg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wmg ProSAT]</span></td></tr>
 </table>
@@ Line 11: / Line 12: @@
 == Function ==
 [[http://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 ==
+Bromodomain and extra-terminal (BET) family proteins are key regulators of gene expression in cancer. Herein, we utilize BRD4 profiling to identify critical pathways involved in pathogenesis of chronic lymphocytic leukemia (CLL). BRD4 is overexpressed in CLL and is enriched proximal to genes upregulated or de novo expressed in CLL with known functions in disease pathogenesis and progression. These genes, including key members of the B-cell receptor (BCR) signaling pathway, provide a rationale for this therapeutic approach to identify new targets in alternative types of cancer. Additionally, we describe PLX51107, a structurally distinct BET inhibitor with novel in vitro and in vivo pharmacologic properties that emulates or exceeds the efficacy of BCR signaling agents in preclinical models of CLL. Herein, the discovery of the involvement of BRD4 in the core CLL transcriptional program provides a compelling rationale for clinical investigation of PLX51107 as epigenetic therapy in CLL and application of BRD4 profiling in other cancers.Significance: To date, functional studies of BRD4 in CLL are lacking. Through integrated genomic, functional, and pharmacologic analyses, we uncover the existence of BRD4-regulated core CLL transcriptional programs and present preclinical proof-of-concept studies validating BET inhibition as an epigenetic approach to target BCR signaling in CLL. Cancer Discov; 8(4); 458-77. (c)2018 AACR.This article is highlighted in the In This Issue feature, p. 371.
+BRD4 Profiling Identifies Critical Chronic Lymphocytic Leukemia Oncogenic Circuits and Reveals Sensitivity to PLX51107, a Novel Structurally Distinct BET Inhibitor.,Ozer HG, El-Gamal D, Powell B, Hing ZA, Blachly JS, Harrington B, Mitchell S, Grieselhuber NR, Williams K, Lai TH, Alinari L, Baiocchi RA, Brinton L, Baskin E, Cannon M, Beaver L, Goettl VM, Lucas DM, Woyach JA, Sampath D, Lehman AM, Yu L, Zhang J, Ma Y, Zhang Y, Spevak W, Shi S, Severson P, Shellooe R, Carias H, Tsang G, Dong K, Ewing T, Marimuthu A, Tantoy C, Walters J, Sanftner L, Rezaei H, Nespi M, Matusow B, Habets G, Ibrahim P, Zhang C, Mathe EA, Bollag G, Byrd JC, Lapalombella R Cancer Discov. 2018 Apr;8(4):458-477. doi: 10.1158/2159-8290.CD-17-0902. Epub, 2018 Jan 31. PMID:29386193<ref>PMID:29386193</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 5wmg" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Zhang, Y]]
 [[Category: Brd4]]

5wmg

From Proteopedia

Revision as of 09:40, 13 February 2019

N-terminal bromodomain of BRD4 in complex with OTX-015

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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