5II1

Crystal Structure of the fifth bromodomain of human polybromo (PB1) in complex with 1-methylisochromeno[3,4-c]pyrazol-5(3H)-one

5II1 の概要

• エントリーDOI: 10.2210/pdb5ii1/pdb
• 分子名称: Protein polybromo-1, 1-methyl[2]benzopyrano[3,4-c]pyrazol-5(3H)-one (3 entities in total)
• 機能のキーワード: bromodomain, complex, small molecule, structural genomics consortium, sgc, transcription
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus: Q86U86
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 29696.39

構造登録者

Filippakopoulos, P.,Picaud, S.,Felletar, I.,Myrianthopoulos, V.,Mikros, E.,von Delft, F.,Edwards, A.M.,Arrowsmith, C.H.,Bountra, C.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2016-03-01, 公開日: 2016-06-29, 最終更新日: 2024-01-10)

主引用文献

Myrianthopoulos, V.,Gaboriaud-Kolar, N.,Tallant, C.,Hall, M.L.,Grigoriou, S.,Brownlee, P.M.,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, A.L.,Downs, J.A.,Knapp, S.,Mikros, E.
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.
J.Med.Chem., 59:8787-8803, 2016

PubMed Abstract: 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 μM and an excellent selectivity profile, thus comprising a promising lead for the development of chemical probes targeting PB1(5).

PubMed: 27617704
DOI: 10.1021/acs.jmedchem.6b00355

実験手法

X-RAY DIFFRACTION (2.02 Å)