3MXF

Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor JQ1

Summary for 3MXF

• Entry DOI: 10.2210/pdb3mxf/pdb
• Descriptor: Bromodomain-containing protein 4, (6S)-6-(2-tert-butoxy-2-oxoethyl)-4-(4-chlorophenyl)-2,3,9-trimethyl-6,7-dihydrothieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-10-ium, IODIDE ION, ... (6 entities in total)
• Functional Keywords: bromodomain-containing protein 4 isoform long, brd4, bromodomain containing protein 4, cap, hunk1, mcap, mitotic chromosome associated protein, jq1, betsoff1, structural genomics consortium, sgc, cell cycle
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus (By similarity): O60885
• Total number of polymer chains: 1
• Total formula weight: 15948.62

Authors

Filippakopoulos, P.,Picaud, S.,Qi, J.,Keates, T.,Felletar, I.,Fedorov, O.,Muniz, J.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Weigelt, J.,Bountra, C.,Bradner, J.E.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2010-05-07, release date: 2010-10-06, Last modification date: 2023-09-06)

Primary citation

Filippakopoulos, P.,Qi, J.,Picaud, S.,Shen, Y.,Smith, W.B.,Fedorov, O.,Morse, E.M.,Keates, T.,Hickman, T.T.,Felletar, I.,Philpott, M.,Munro, S.,McKeown, M.R.,Wang, Y.,Christie, A.L.,West, N.,Cameron, M.J.,Schwartz, B.,Heightman, T.D.,La Thangue, N.,French, C.A.,Wiest, O.,Kung, A.L.,Knapp, S.,Bradner, J.E.
Selective inhibition of BET bromodomains.
Nature, 468:1067-1073, 2010

PubMed Abstract: Epigenetic proteins are intently pursued targets in ligand discovery. So far, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic 'writers' and 'erasers'. Potent inhibitors of histone binding modules have not yet been described. Here we report a cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains. High potency and specificity towards a subset of human bromodomains is explained by co-crystal structures with bromodomain and extra-terminal (BET) family member BRD4, revealing excellent shape complementarity with the acetyl-lysine binding cavity. Recurrent translocation of BRD4 is observed in a genetically-defined, incurable subtype of human squamous carcinoma. Competitive binding by JQ1 displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific antiproliferative effects in BRD4-dependent cell lines and patient-derived xenograft models. These data establish proof-of-concept for targeting protein-protein interactions of epigenetic 'readers', and provide a versatile chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family.

PubMed: 20871596
DOI: 10.1038/nature09504

Experimental method

X-RAY DIFFRACTION (1.6 Å)