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6uwx

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Cocrystal of BRD4(D1) with a ethyl carbamate thiazepane inhibitor

Structural highlights

6uwx is a 1 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 1.307Å
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

Fragment-based ligand discovery has been successful in targeting diverse proteins. Despite drug-like molecules having more 3D character, traditional fragment libraries are largely composed of flat, aromatic fragments. The use of 3D-enriched fragments for enhancing library diversity is underexplored especially against protein-protein interactions. Here, we evaluate using 3D-enriched fragments against bromodomains. Bromodomains are highly ligandable, but selectivity remains challenging, particularly for bromodomain and extraterminal (BET) family bromodomains. We screened a 3D-enriched fragment library against BRD4(D1) via (1)H CPMG NMR with a protein-observed (19)F NMR secondary assay. The screen led to 29% of the hits that are selective over two related bromodomains, BRDT(D1) and BPTF, and the identification of underrepresented chemical bromodomain inhibitor scaffolds. Initial structure-activity relationship studies guided by X-ray crystallography led to a ligand-efficient thiazepane, with good selectivity and affinity for BET bromodomains. These results suggest that the incorporation of 3D-enriched fragments to increase library diversity can benefit bromodomain screening.

Evaluating the Advantages of Using 3D-Enriched Fragments for Targeting BET Bromodomains.,Johnson JA, Nicolaou CA, Kirberger SE, Pandey AK, Hu H, Pomerantz WCK ACS Med Chem Lett. 2019 Nov 22;10(12):1648-1654. doi:, 10.1021/acsmedchemlett.9b00414. eCollection 2019 Dec 12. PMID:31857841^[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
↑ Johnson JA, Nicolaou CA, Kirberger SE, Pandey AK, Hu H, Pomerantz WCK. Evaluating the Advantages of Using 3D-Enriched Fragments for Targeting BET Bromodomains. ACS Med Chem Lett. 2019 Nov 22;10(12):1648-1654. doi:, 10.1021/acsmedchemlett.9b00414. eCollection 2019 Dec 12. PMID:31857841 doi:http://dx.doi.org/10.1021/acsmedchemlett.9b00414

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/6uwx"

Categories: Homo sapiens | Large Structures | Johnson JA | Pomerantz WCK

@@ Line 3: / Line 3: @@
 <StructureSection load='6uwx' size='340' side='right'caption='[[6uwx]], [[Resolution|resolution]] 1.31&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6uwx]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6UWX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6UWX FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6uwx]] is a 1 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=6UWX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6UWX 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=QKD:ethyl+(7S)-7-(thiophen-2-yl)-1,4-thiazepane-4-carboxylate'>QKD</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]] 1.307&#8491;</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=6uwx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uwx OCA], [http://pdbe.org/6uwx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6uwx RCSB], [http://www.ebi.ac.uk/pdbsum/6uwx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6uwx ProSAT]</span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=QKD:ethyl+(7S)-7-(thiophen-2-yl)-1,4-thiazepane-4-carboxylate'>QKD</scene></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=6uwx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uwx OCA], [https://pdbe.org/6uwx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6uwx RCSB], [https://www.ebi.ac.uk/pdbsum/6uwx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6uwx 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 20: / Line 21: @@
 </div>
 <div class="pdbe-citations 6uwx" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Johnson, J A]]
+[[Category: Johnson JA]]
-[[Category: Pomerantz, W C.K]]
+[[Category: Pomerantz WCK]]
-[[Category: Gene regulation-inhibitor complex]]
-[[Category: Inhibitor]]

6uwx

From Proteopedia

Current revision

Cocrystal of BRD4(D1) with a ethyl carbamate thiazepane inhibitor

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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