9Z4A

Cryo-EM structure of the human PRMT5:MEP50:pICln complex at a 4:3:4 stoichiometric ratio

Summary for 9Z4A

• Entry DOI: 10.2210/pdb9z4a/pdb
• EMDB information: 73801
• Descriptor: Protein arginine N-methyltransferase 5, N-terminally processed, Methylosome protein WDR77, Methylosome subunit pICln, ... (4 entities in total)
• Functional Keywords: arginine methyltransferase, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 11
• Total formula weight: 401262.63

Authors

Xu, X.,Chi, Z.,Jiang, W.,Li, C. (deposition date: 2025-11-09, release date: 2026-09-16)

Primary citation

Chi, Z.,Xu, X.,Shen, Z.,Deng, X.,Elzey, B.D.,Li, C.,Jiang, W.,Hu, C.D.
Cryo-EM structure-based discovery of etravirine as a specific inhibitor of PRMT5/pICln protein-protein interaction for prostate cancer treatment.
J Enzyme Inhib Med Chem, 41:2727844-2727844, 2026

PubMed Abstract: Protein arginine methyltransferase 5 (PRMT5) is overexpressed in many cancers and correlates with poor patient survival. In prostate cancer, PRMT5 cooperates with its cofactor pICln to promote tumour growth by epigenetically activating androgen receptor (AR) expression. Using a near-atomic cryo-EM structure of PRMT5/MEP50/pICln complex, we identified a previously undefined, pICln-specific protein-protein interaction (PPI) interface on PRMT5, termed P4I. Structure-based virtual screening identified the FDA-approved compound etravirine as a binder to this site. BiFC, Co-IP, and PLA assays confirmed that etravirine disrupts PRMT5/pICln interaction. A cryo-EM structure of PRMT5/MEP50/etravirine further validated on-target binding at P4I. Functionally, etravirine reduced prostate cancer cell proliferation, inhibited tumour growth, and downregulated AR and AR-V7 expression in cells and in mouse models. These results demonstrate that the unique P4I interface is a promising therapeutic target and that etravirine serves as a proof-of-concept lead compound for exploring the potential of P4I-targeted strategies in prostate cancer.

PubMed: 42710907
DOI: 10.1080/14756366.2026.2727844

Experimental method

ELECTRON MICROSCOPY (3.84 Å)