7S3P

BD2 domain of human BRD3 bound to Physachenolide C

Summary for 7S3P

• Entry DOI: 10.2210/pdb7s3p/pdb
• Descriptor: Bromodomain-containing protein 3, Physachenolide C, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: inhibitor, bromodomain, epigenetics, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 11
• Total formula weight: 150833.80

Authors

Horton, N.C.,Chapman, E.,Sivinski, J.,Zerio, C.,Ghadirian, N. (deposition date: 2021-09-07, release date: 2023-01-11, Last modification date: 2023-10-25)

Primary citation

Zerio, C.J.,Sivinski, J.,Wijeratne, E.M.K.,Xu, Y.M.,Ngo, D.T.,Ambrose, A.J.,Villa-Celis, L.,Ghadirian, N.,Clarkson, M.W.,Zhang, D.D.,Horton, N.C.,Gunatilaka, A.A.L.,Fromme, R.,Chapman, E.
Physachenolide C is a Potent, Selective BET Inhibitor.
J.Med.Chem., 66:913-933, 2023

PubMed Abstract: A pulldown using a biotinylated natural product of interest in the 17β-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.

PubMed: 36577036
DOI: 10.1021/acs.jmedchem.2c01770

Experimental method

X-RAY DIFFRACTION (2.89 Å)