4MR5
Crystal Structure of the second bromodomain of human BRD2 in complex with a quinazolinone ligand (RVX-OH)
Summary for 4MR5
| Entry DOI | 10.2210/pdb4mr5/pdb |
| Related | 4MR3 4mr4 4mr6 |
| Descriptor | Bromodomain-containing protein 2, 1,2-ETHANEDIOL, DIMETHYL SULFOXIDE, ... (5 entities in total) |
| Functional Keywords | brd2, ring3, small molecule inhibitor, rvx-oh, inhibitor complex, structural genomics consortium, sgc, transcription-transcription inhibitor complex, transcription/transcription inhibitor |
| Biological source | Homo sapiens (human) |
| Cellular location | Nucleus (Probable): P25440 |
| Total number of polymer chains | 1 |
| Total formula weight | 14072.21 |
| Authors | Filippakopoulos, P.,Picaud, S.,Felletar, I.,Martin, S.,Fedorov, O.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Weigelt, J.,Bountra, C.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2013-09-17, release date: 2013-11-27, Last modification date: 2024-02-28) |
| Primary citation | Picaud, S.,Wells, C.,Felletar, I.,Brotherton, D.,Martin, S.,Savitsky, P.,Diez-Dacal, B.,Philpott, M.,Bountra, C.,Lingard, H.,Fedorov, O.,Muller, S.,Brennan, P.E.,Knapp, S.,Filippakopoulos, P. RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain. Proc.Natl.Acad.Sci.USA, 110:19754-19759, 2013 Cited by PubMed Abstract: Bromodomains have emerged as attractive candidates for the development of inhibitors targeting gene transcription. Inhibitors of the bromo and extraterminal (BET) family recently showed promising activity in diverse disease models. However, the pleiotropic nature of BET proteins regulating tissue-specific transcription has raised safety concerns and suggested that attempts should be made for domain-specific targeting. Here, we report that RVX-208, a compound currently in phase II clinical trials, is a BET bromodomain inhibitor specific for second bromodomains (BD2s). Cocrystal structures revealed binding modes of RVX-208 and its synthetic precursor, and fluorescent recovery after photobleaching demonstrated that RVX-208 displaces BET proteins from chromatin. However, gene-expression data showed that BD2 inhibition only modestly affects BET-dependent gene transcription. Our data demonstrate the feasibility of specific targeting within the BET family resulting in different transcriptional outcomes and highlight the importance of BD1 in transcriptional regulation. PubMed: 24248379DOI: 10.1073/pnas.1310658110 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.63 Å) |
Structure validation
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