View source for 5ii1


==Crystal Structure of the fifth bromodomain of human polybromo (PB1) in complex with 1-methylisochromeno[3,4-c]pyrazol-5(3H)-one==
<StructureSection load='5ii1' size='340' side='right'caption='[[5ii1]], [[Resolution|resolution]] 2.02&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5ii1]] is a 2 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=5II1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5II1 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]] 2.02&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6BL:1-METHYL[2]BENZOPYRANO[3,4-C]PYRAZOL-5(3H)-ONE'>6BL</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=5ii1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ii1 OCA], [https://pdbe.org/5ii1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ii1 RCSB], [https://www.ebi.ac.uk/pdbsum/5ii1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ii1 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/PB1_HUMAN PB1_HUMAN] Defects in PBRM1 are a cause of renal cell carcinoma (RCC) [MIM:[https://omim.org/entry/144700 144700]. It is a heterogeneous group of sporadic or hereditary carcinoma derived from cells of the proximal renal tubular epithelium. It is subclassified into clear cell renal carcinoma (non-papillary carcinoma), papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma with medullary carcinoma of the kidney, and unclassified renal cell carcinoma.<ref>PMID:21248752</ref> 
== Function ==
[https://www.uniprot.org/uniprot/PB1_HUMAN PB1_HUMAN] Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Acts as a negative regulator of cell proliferation.<ref>PMID:21248752</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Bromodomains (BRDs) are epigenetic interaction domains currently recognized as emerging drug targets for development of anticancer or anti-inflammatory agents. In this study, development of a selective ligand of the fifth BRD of polybromo protein-1 (PB1(5)) related to switch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complexes is presented. A compound collection was evaluated by consensus virtual screening and a hit was identified. The biophysical study of protein-ligand interactions was performed using X-ray crystallography and isothermal titration calorimetry. Collective data supported the hypothesis that affinity improvement could be achieved by enhancing interactions of the complex with the solvent. The derived SAR along with free energy calculations and a consensus hydration analysis using WaterMap and SZmap algorithms guided rational design of a set of novel analogues. The most potent analogue demonstrated high affinity of 3.3 muM and an excellent selectivity profile, thus comprising a promising lead for the development of chemical probes targeting PB1(5).

Discovery and Optimization of a Selective Ligand for the Switch/Sucrose Nonfermenting-Related Bromodomains of Polybromo Protein-1 by the Use of Virtual Screening and Hydration Analysis.,Myrianthopoulos V, Gaboriaud-Kolar N, Tallant C, Hall ML, Grigoriou S, Brownlee PM, Fedorov O, Rogers C, Heidenreich D, Wanior M, Drosos N, Mexia N, Savitsky P, Bagratuni T, Kastritis E, Terpos E, Filippakopoulos P, Muller S, Skaltsounis AL, Downs JA, Knapp S, Mikros E J Med Chem. 2016 Oct 13;59(19):8787-8803. Epub 2016 Sep 27. PMID:27617704<ref>PMID:27617704</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5ii1" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Arrowsmith CH]]
[[Category: Bountra C]]
[[Category: Edwards AM]]
[[Category: Felletar I]]
[[Category: Filippakopoulos P]]
[[Category: Knapp S]]
[[Category: Mikros E]]
[[Category: Myrianthopoulos V]]
[[Category: Picaud S]]
[[Category: Von Delft F]]