4MEN
Crystal Structure of the first bromodomain of human BRD4 in complex with a 5-methyl-triazolopyrimidine ligand
Summary for 4MEN
| Entry DOI | 10.2210/pdb4men/pdb |
| Related | 4MEO 4MEP 4MEQ |
| Descriptor | Bromodomain-containing protein 4, 1,2-ETHANEDIOL, N,5-dimethyl-N-(4-methylbenzyl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine, ... (4 entities in total) |
| Functional Keywords | brd4, cap, hunk1, mcap, mitotic chromosome associated protein, brd, small molecule inhibitor, structural genomics consortium, sgc, transcription-transcription inhibitor complex, transcription/transcription inhibitor |
| Biological source | Homo sapiens (human) |
| Cellular location | Nucleus: O60885 |
| Total number of polymer chains | 1 |
| Total formula weight | 15428.78 |
| Authors | Filippakopoulos, P.,Picaud, S.,Felletar, I.,Martin, S.,Fedorov, O.,Vidler, L.R.,Brown, N.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Weigelt, J.,Bountra, C.,Hoelder, S.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2013-08-27, release date: 2013-09-25, Last modification date: 2023-09-20) |
| Primary citation | Vidler, L.R.,Filippakopoulos, P.,Fedorov, O.,Picaud, S.,Martin, S.,Tomsett, M.,Woodward, H.,Brown, N.,Knapp, S.,Hoelder, S. Discovery of Novel Small-Molecule Inhibitors of BRD4 Using Structure-Based Virtual Screening. J.Med.Chem., 56:8073-8088, 2013 Cited by PubMed Abstract: Bromodomains (BRDs) are epigenetic readers that recognize acetylated-lysine (KAc) on proteins and are implicated in a number of diseases. We describe a virtual screening approach to identify BRD inhibitors. Key elements of this approach are the extensive design and use of substructure queries to compile a set of commercially available compounds featuring novel putative KAc mimetics and docking this set for final compound selection. We describe the validation of this approach by applying it to the first BRD of BRD4. The selection and testing of 143 compounds lead to the discovery of six novel hits, including four unprecedented KAc mimetics. We solved the crystal structure of four hits, determined their binding mode, and improved their potency through synthesis and the purchase of derivatives. This work provides a validated virtual screening approach that is applicable to other BRDs and describes novel KAc mimetics that can be further explored to design more potent inhibitors. PubMed: 24090311DOI: 10.1021/jm4011302 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.81 Å) |
Structure validation
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