6b3w: Difference between revisions

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-'''Unreleased structure'''
-The entry 6b3w is ON HOLD  until Paper Publication
+==Structure of Hs/AcPRC2 in complex with 5,8-dichloro-7-(3,5-dimethyl-1,2-oxazol-4-yl)-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3,4-dihydroisoquinolin-1(2H)-one==
+<StructureSection load='6b3w' size='340' side='right'caption='[[6b3w]], [[Resolution|resolution]] 3.05&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6b3w]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Anolis_carolinensis Anolis carolinensis] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6B3W OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6B3W 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]] 3.05&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CJG:5,8-bis(chloranyl)-7-(3,5-dimethyl-1,2-oxazol-4-yl)-2-[(4,6-dimethyl-2-oxidanylidene-1~{H}-pyridin-3-yl)methyl]-3,4-dihydroisoquinolin-1-one'>CJG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=6b3w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6b3w OCA], [https://pdbe.org/6b3w PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6b3w RCSB], [https://www.ebi.ac.uk/pdbsum/6b3w PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6b3w ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/G1KPH4_ANOCA G1KPH4_ANOCA]
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+A new series of lactam-derived EZH2 inhibitors was designed via a ligand- and physicochemical property-based strategy to address metabolic stability and thermodynamic solubility issues associated with previous lead compound 1. The new inhibitors incorporated an sp3 hybridized carbon atom at the 7-position of the lactam moiety present in lead compound 1 as a replacement for a dimethylisoxazole group. This transformation enabled optimization of the physicochemical properties and potency compared to compound 1. Analysis of relationships between calculated logD (cLogD) values and in vitro metabolic stability and permeability parameters identified a clogD range that afforded an increased probability of achieving favorable ADME data in a single molecule. Compound 23a exhibited the best overlap of potency and pharmaceutical properties as well as robust tumor growth inhibition in vivo and was therefore advanced as a development candidate (PF-06821497). A crystal structure of 23a in complex with the three-protein PRC2 complex enabled understanding of the key structural features required for optimal binding.
-Authors: Gajiwala, K.S., Brooun, A., Liu, W., Deng, Y., Stewart, A.E.
+Optimization of orally bioavailable enhancer of zeste homolog 2 (EZH2) inhibitors using ligand and property-based design strategies: Identification of development candidate (R)-5,8-dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2- dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (PF-06821497).,Kung PP, Bingham P, Brooun A, Collins MR, Deng YL, Dinh DM, Fan C, Gajiwala KS, Grantner R, Gukasyan HJ, Hu W, Huang B, Kania RS, Kephart SE, Krivacic CT, Kumpf RA, Khamphavong P, Kraus M, Liu W, Maegley KA, Nguyen L, Ren S, Richter DT, Rollins RA, Sach NW, Sharma S, Sherrill J, Spangler JE, Stewart AE, Sutton SC, Uryu S, Verhelle D, Wang H, Wang S, Wythes M, Xin S, Yamazaki S, Zhu H, Zhu J, Zehnder L, Edwards MP J Med Chem. 2017 Dec 6. doi: 10.1021/acs.jmedchem.7b01375. PMID:29211475<ref>PMID:29211475</ref>
-Description: Structure of Hs/AcPRC2 in complex with 5,8-dichloro-7-(3,5-dimethyl-1,2-oxazol-4-yl)-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3,4-dihydroisoquinolin-1(2H)-one
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Stewart, A.E]]
+<div class="pdbe-citations 6b3w" style="background-color:#fffaf0;"></div>
-[[Category: Liu, W]]
-[[Category: Gajiwala, K.S]]
+==See Also==
-[[Category: Deng, Y]]
+*[[Polycomb complex proteins 3D structures|Polycomb complex proteins 3D structures]]
-[[Category: Brooun, A]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Anolis carolinensis]]
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Brooun A]]
+[[Category: Deng Y]]
+[[Category: Gajiwala KS]]
+[[Category: Liu W]]
+[[Category: Stewart AE]]