4z93 | pdb_00004z93

BRD4 bromodomain 2 in complex with gamma-carboline-containing compound, number 18.

spinqualitylabelsall models 4z93, resolution 1.27Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4z93 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.27Å Ligands: 4LD, CME, EDO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease BRD4_HUMAN Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein. Function BRD4_HUMAN Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). Publication Abstract from PubMed Small-molecule inhibitors of bromodomain and extra terminal proteins (BET), including BRD2, BRD3, and BRD4 proteins have therapeutic potential for the treatment of human cancers and other diseases and conditions. In this paper, we report the design, synthesis, and evaluation of gamma-carboline-containing compounds as a new class of small-molecule BET inhibitors. The most potent inhibitor (compound 18, RX-37) obtained from this study binds to BET bromodomain proteins (BRD2, BRD3, and BRD4) with Ki values of 3.2-24.7 nM and demonstrates high selectivity over other non-BET bromodomain-containing proteins. Compound 18 potently and selectively inhibits cell growth in human acute leukemia cell lines harboring the rearranged mixed lineage leukemia 1 gene. We have determined a cocrystal structure of 18 in complex with BRD4 BD2 at 1.4 A resolution, which provides a solid structural basis for the compound's high binding affinity and for its further structure-based optimization. Compound 18 represents a promising lead compound for the development of a new class of therapeutics for the treatment of human cancer and other conditions. Structure-Based Design of gamma-Carboline Analogues as Potent and Specific BET Bromodomain Inhibitors.,Ran X, Zhao Y, Liu L, Bai L, Yang CY, Zhou B, Meagher JL, Chinnaswamy K, Stuckey JA, Wang S J Med Chem. 2015 Jun 25;58(12):4927-39. doi: 10.1021/acs.jmedchem.5b00613. Epub, 2015 Jun 16. PMID:26080064 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Bromodomain-containing protein 3D structures

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