6dmk

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'''Unreleased structure'''
 
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The entry 6dmk is ON HOLD
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==A multiconformer ligand model of an isoxazolyl-benzimidazole ligand bound to the bromodomain of human CREBBP==
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<StructureSection load='6dmk' size='340' side='right' caption='[[6dmk]], [[Resolution|resolution]] 1.66&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[6dmk]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DMK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DMK 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=2LL:5-(3,5-DIMETHYL-1,2-OXAZOL-4-YL)-1-[2-(MORPHOLIN-4-YL)ETHYL]-2-(2-PHENYLETHYL)-1H-BENZIMIDAZOLE'>2LL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4nr5|4nr5]]</td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Histone_acetyltransferase Histone acetyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.48 2.3.1.48] </span></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=6dmk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dmk OCA], [http://pdbe.org/6dmk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6dmk RCSB], [http://www.ebi.ac.uk/pdbsum/6dmk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6dmk ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[[http://www.uniprot.org/uniprot/CBP_HUMAN CBP_HUMAN]] Note=Chromosomal aberrations involving CREBBP may be a cause of acute myeloid leukemias. Translocation t(8;16)(p11;p13) with KAT6A; translocation t(11;16)(q23;p13.3) with MLL/HRX; translocation t(10;16)(q22;p13) with KAT6B. KAT6A-CREBBP may induce leukemia by inhibiting RUNX1-mediated transcription. Defects in CREBBP are a cause of Rubinstein-Taybi syndrome type 1 (RSTS1) [MIM:[http://omim.org/entry/180849 180849]]. RSTS1 is an autosomal dominant disorder characterized by craniofacial abnormalities, broad thumbs, broad big toes, mental retardation and a propensity for development of malignancies.<ref>PMID:11331617</ref> <ref>PMID:12114483</ref> <ref>PMID:12566391</ref> <ref>PMID:15706485</ref>
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== Function ==
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[[http://www.uniprot.org/uniprot/CBP_HUMAN CBP_HUMAN]] Acetylates histones, giving a specific tag for transcriptional activation. Also acetylates non-histone proteins, like NCOA3 and FOXO1. Binds specifically to phosphorylated CREB and enhances its transcriptional activity toward cAMP-responsive genes. Acts as a coactivator of ALX1 in the presence of EP300.<ref>PMID:9707565</ref> <ref>PMID:11154691</ref> <ref>PMID:12738767</ref> <ref>PMID:12929931</ref>
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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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Authors:
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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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Description:
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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<div class="pdbe-citations 6dmk" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Histone acetyltransferase]]
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[[Category: Bedem, H van den]]
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[[Category: Borrelli, K]]
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[[Category: Day, T]]
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[[Category: Fonseca, R]]
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[[Category: Fraser, J S]]
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[[Category: Heliou, A]]
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[[Category: Hudson, B M]]
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[[Category: Keedy, D]]
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[[Category: Suresh, P]]
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[[Category: Zundert, G van]]
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[[Category: Complex]]
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[[Category: Multi conformer model]]
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[[Category: Transcription]]
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[[Category: Transcription-transcription inhibitor complex]]

Revision as of 08:24, 19 December 2018

A multiconformer ligand model of an isoxazolyl-benzimidazole ligand bound to the bromodomain of human CREBBP

6dmk, resolution 1.66Å

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