5ktu

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m (Protected "5ktu" [edit=sysop:move=sysop])
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'''Unreleased structure'''
 
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The entry 5ktu is ON HOLD until Paper Publication
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==Crystal structure of the bromodomain of human CREBBP bound to pyrazolopiperidine scaffold==
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<StructureSection load='5ktu' size='340' side='right' caption='[[5ktu]], [[Resolution|resolution]] 1.38&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[5ktu]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KTU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5KTU 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=6XB:1-(3-PHENYLAZANYL-1,4,6,7-TETRAHYDROPYRAZOLO[4,3-C]PYRIDIN-5-YL)ETHANONE'>6XB</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene></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=5ktu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ktu OCA], [http://pdbe.org/5ktu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ktu RCSB], [http://www.ebi.ac.uk/pdbsum/5ktu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ktu 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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The single bromodomain of the closely related transcriptional regulators CBP/EP300 is a target of much recent interest in cancer and immune system regulation. A co-crystal structure of a ligand-efficient screening hit and the CBP bromodomain guided initial design targeting the LPF shelf, ZA loop, and acetylated lysine binding regions. Structure-activity relationship studies allowed us to identify a more potent analogue. Optimization of permeability and microsomal stability and subsequent improvement of mouse hepatocyte stability afforded 59 (GNE-272, TR-FRET IC50 = 0.02 muM, BRET IC50 = 0.41 muM, BRD4(1) IC50 = 13 muM) that retained the best balance of cell potency, selectivity, and in vivo PK. Compound 59 showed a marked antiproliferative effect in hematologic cancer cell lines and modulates MYC expression in vivo that corresponds with antitumor activity in an AML tumor model.
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Authors: Jayaram, H., Poy, F., Setser, J.W., Bellon, S.F.
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Discovery of a Potent and Selective in Vivo Probe (GNE-272) for the Bromodomains of CBP/EP300.,Crawford TD, Romero FA, Lai KW, Tsui V, Taylor AM, de Leon Boenig G, Noland CL, Murray J, Ly J, Choo EF, Hunsaker TL, Chan EW, Merchant M, Kharbanda S, Gascoigne KE, Kaufman S, Beresini MH, Liao J, Liu W, Chen KX, Chen Z, Conery AR, Cote A, Jayaram H, Jiang Y, Kiefer JR, Kleinheinz T, Li Y, Maher J, Pardo E, Poy F, Spillane KL, Wang F, Wang J, Wei X, Xu Z, Xu Z, Yen I, Zawadzke L, Zhu X, Bellon S, Cummings R, Cochran AG, Albrecht BK, Magnuson S J Med Chem. 2016 Sep 28. PMID:27682507<ref>PMID:27682507</ref>
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Description: Crystal structure of the bromodomain of human CREBBP bound to pyrazolopiperidine scaffold
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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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[[Category: Poy, F]]
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<div class="pdbe-citations 5ktu" 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: Bellon, S F]]
[[Category: Jayaram, H]]
[[Category: Jayaram, H]]
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[[Category: Bellon, S.F]]
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[[Category: Poy, F]]
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[[Category: Setser, J.W]]
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[[Category: Setser, J W]]
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[[Category: Bromodomain]]
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[[Category: Epigenetic]]
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[[Category: Inhibitor]]
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[[Category: Transferase]]

Revision as of 18:15, 2 November 2016

Crystal structure of the bromodomain of human CREBBP bound to pyrazolopiperidine scaffold

5ktu, resolution 1.38Å

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