5II1

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

Summary for 5II1

• Entry DOI: 10.2210/pdb5ii1/pdb
• Descriptor: Protein polybromo-1, 1-methyl[2]benzopyrano[3,4-c]pyrazol-5(3H)-one (3 entities in total)
• Functional Keywords: bromodomain, complex, small molecule, structural genomics consortium, sgc, transcription
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: Q86U86
• Total number of polymer chains: 2
• Total formula weight: 29696.39

Authors

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) (deposition date: 2016-03-01, release date: 2016-06-29, Last modification date: 2024-01-10)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.02 Å)