7s3p

BD2 domain of human BRD3 bound to Physachenolide C

spinqualitylabelsall models 7s3p, resolution 2.89Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7s3p is a 11 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 2.89Å Ligands: 8L6, CL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease BRD3_HUMAN Note=A chromosomal aberration involving BRD3 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;9)(q14;q34) with NUT which produces a BRD3-NUT fusion protein. Function BRD3_HUMAN Binds hyperacetylated chromatin and plays a role in the regulation of transcription, probably by chromatin remodeling and interaction with transcription factors. Regulates transcription by promoting the binding of the transcription factor GATA1 to its targets (By similarity). Regulates transcription of the CCND1 gene. Publication Abstract from PubMed A pulldown using a biotinylated natural product of interest in the 17beta-hydroxywithanolide (17-BHW) class, physachenolide C (PCC), identified the bromodomain and extra-terminal domain (BET) family of proteins (BRD2, BRD3, and BRD4), readers of acetyl-lysine modifications and regulators of gene transcription, as potential cellular targets. BROMOscan bromodomain profiling and biochemical assays support PCC as a BET inhibitor with increased selectivity for bromodomain (BD)-1 of BRD3 and BRD4, and X-ray crystallography and NMR studies uncovered specific contacts that underlie the potency and selectivity of PCC toward BRD3-BD1 over BRD3-BD2. PCC also displays characteristics of a molecular glue, facilitating proteasome-mediated degradation of BRD3 and BRD4. Finally, PCC is more potent than other withanolide analogues and gold-standard pan-BET inhibitor (+)-JQ1 in cytotoxicity assays across five prostate cancer (PC) cell lines regardless of androgen receptor (AR)-signaling status. Physachenolide C is a Potent, Selective BET Inhibitor.,Zerio CJ, Sivinski J, Wijeratne EMK, Xu YM, Ngo DT, Ambrose AJ, Villa-Celis L, Ghadirian N, Clarkson MW, Zhang DD, Horton NC, Gunatilaka AAL, Fromme R, Chapman E J Med Chem. 2022 Dec 28. doi: 10.1021/acs.jmedchem.2c01770. PMID:36577036 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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