4tqn: Difference between revisions
New page: '''Unreleased structure''' The entry 4tqn is ON HOLD Authors: Dong, J, Caflisch, A Description: Crystal structure of the bromodomain of human CREBBP in complex with UL04 |
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==Crystal structure of the bromodomain of human CREBBP in complex with UL04== | |||
<StructureSection load='4tqn' size='340' side='right'caption='[[4tqn]], [[Resolution|resolution]] 1.70Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4tqn]] 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=4TQN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4TQN FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.7Å</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=UL4:3-[(5-ACETYL-2-ETHOXYPHENYL)CARBAMOYL]BENZOIC+ACID'>UL4</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=4tqn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tqn OCA], [https://pdbe.org/4tqn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4tqn RCSB], [https://www.ebi.ac.uk/pdbsum/4tqn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4tqn ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://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:[https://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> | |||
== Function == | |||
[https://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> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
We have identified two chemotypes of CREBBP bromodomain ligands by fragment-based virtual screening. First a library of about 100,000 molecular fragments was docked with evaluation of force field energy and desolvation penalty. Then the top ranking fragments were used for selecting molecules for flexible docking from a library of nearly two million compounds. Upon flexible docking and ranking, only 17 molecules from the two-million library were tested in vitro, and two of them showed an equilibrium dissociation constant smaller than 30 microM. The 4-acyl pyrrole hit 1 was optimized by taking into account the binding mode obtained by docking and molecular dynamics simulations which suggested how to improve the interactions with the side chain of Arg1173 at the rim of the binding site. The efficient hit optimization (only two synthesized derivatives) yielded the 4-acyl pyrrole derivative 6 which shows a single-digit micromolar affinity for the CREBBP bromodomain and a ligand efficiency of 0.34 kcal/mol per non-hydrogen atom. The acyl benzene hit 9 was also optimized by improving the polar interactions with the side chain of Arg1173, which resulted in a series of derivatives with nanomolar potencies, good ligand efficiency as well as high selectivity (see back to back paper). The in silico predicted binding mode of the acyl benzene derivative 10 was validated by solving the structure of the complex with the CREBBP bromodomain. | |||
Discovery of CREBBP Bromodomain Inhibitors by High-throughput Docking and Hit Optimization Guided by Molecular Dynamics.,Xu M, Unzue A, Dong J, Spiliotopoulos D, Nevado C, Caflisch A J Med Chem. 2015 Jun 30. PMID:26125948<ref>PMID:26125948</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4tqn" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[CREB-binding protein 3D structures|CREB-binding protein 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Caflisch A]] | |||
[[Category: Dong J]] | |||