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6dml

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==A multiconformer ligand model of 3,5 dimethylisoxaxole bound to the bromodomain of human BRD4==
==A multiconformer ligand model of 3,5 dimethylisoxaxole bound to the bromodomain of human BRD4==
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<StructureSection load='6dml' size='340' side='right' caption='[[6dml]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
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<StructureSection load='6dml' size='340' side='right'caption='[[6dml]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6dml]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DML OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DML FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6dml]] 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=6DML OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DML FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9BM:4-((2-(TERT-BUTYL)PHENYL)AMINO)-7-(3,5-DIMETHYLISOXAZOL-4-YL)-6-METHOXY-1,5-NAPHTHYRIDINE-3-CARBOXYLIC+ACID'>9BM</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.5&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4bw3|4bw3]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9BM:4-((2-(TERT-BUTYL)PHENYL)AMINO)-7-(3,5-DIMETHYLISOXAZOL-4-YL)-6-METHOXY-1,5-NAPHTHYRIDINE-3-CARBOXYLIC+ACID'>9BM</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
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<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=6dml FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dml OCA], [http://pdbe.org/6dml PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6dml RCSB], [http://www.ebi.ac.uk/pdbsum/6dml PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6dml ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6dml FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dml OCA], [https://pdbe.org/6dml PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6dml RCSB], [https://www.ebi.ac.uk/pdbsum/6dml PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6dml ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
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[[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>
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[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 ==
== Function ==
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[[http://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).
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[https://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Proteins and ligands sample a conformational ensemble that governs molecular recognition, activity, and dissociation. In structure-based drug design, access to this conformational ensemble is critical to understand the balance between entropy and enthalpy in lead optimization. However, ligand conformational heterogeneity is currently severely underreported in crystal structures in the Protein Data Bank, owing in part to a lack of automated and unbiased procedures to model an ensemble of protein-ligand states into X-ray data. Here, we designed a computational method, qFit-ligand, to automatically resolve conformationally averaged ligand heterogeneity in crystal structures, and applied it to a large set of protein receptor-ligand complexes. In an analysis of the cancer related BRD4 domain, we found that up to 29% of protein crystal structures bound with drug-like molecules present evidence of unmodeled, averaged, relatively iso-energetic conformations in ligand-receptor interactions. In many retrospective cases, these alternate conformations were adventitiously exploited to guide compound design, resulting in improved potency or selectivity. Combining qFit-ligand with high-throughput screening or multi-temperature crystallography could therefore augment the structure-based drug design toolbox.
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qFit-ligand reveals widespread conformational heterogeneity of drug-like molecules in X-ray electron density maps.,van Zundert G, Hudson BM, de Oliveira S, Keedy DA, Fonseca R, Heliou A, Suresh P, Borrelli K, Day T, Fraser J, van den Bedem H J Med Chem. 2018 Nov 20. doi: 10.1021/acs.jmedchem.8b01292. PMID:30457858<ref>PMID:30457858</ref>
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==See Also==
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*[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 6dml" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Bedem, H van den]]
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[[Category: Homo sapiens]]
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[[Category: Borrelli, K]]
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[[Category: Large Structures]]
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[[Category: Day, T]]
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[[Category: Borrelli K]]
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[[Category: Fonseca, R]]
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[[Category: Day T]]
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[[Category: Fraser, J S]]
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[[Category: Fonseca R]]
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[[Category: Heliou, A]]
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[[Category: Fraser JS]]
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[[Category: Hudson, B M]]
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[[Category: Heliou A]]
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[[Category: Keedy, D]]
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[[Category: Hudson BM]]
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[[Category: Suresh, P]]
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[[Category: Keedy D]]
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[[Category: Zundert, G van]]
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[[Category: Suresh P]]
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[[Category: Complex]]
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[[Category: Van Zundert G]]
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[[Category: Multiconformer model]]
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[[Category: Van den Bedem H]]
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[[Category: Transcription]]
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[[Category: Transcription-transcription inhibitor complex]]
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Current revision

A multiconformer ligand model of 3,5 dimethylisoxaxole bound to the bromodomain of human BRD4

PDB ID 6dml

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