9z4a

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

spinqualitylabelsall models 9z4a, resolution 3.84Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9z4a 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: Electron Microscopy, Resolution 3.84Å Ligands: SAH Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function ANM5_HUMAN Arginine methyltransferase that can both catalyze the formation of omega-N monomethylarginine (MMA) and symmetrical dimethylarginine (sDMA), with a preference for the formation of MMA. Specifically mediates the symmetrical dimethylation of arginine residues in the small nuclear ribonucleoproteins Sm D1 (SNRPD1) and Sm D3 (SNRPD3); such methylation being required for the assembly and biogenesis of snRNP core particles. Methylates SUPT5H. Mono- and dimethylates arginine residues of myelin basic protein (MBP) in vitro. Plays a role in the assembly of snRNP core particles. May play a role in cytokine-activated transduction pathways. Negatively regulates cyclin E1 promoter activity and cellular proliferation. May regulate the SUPT5H transcriptional elongation properties. May be part of a pathway that is connected to a chloride current, possibly through cytoskeletal rearrangement. Methylates histone H2A and H4 'Arg-3' during germ cell development. Methylates histone H3 'Arg-8', which may repress transcription. Methylates the Piwi proteins (PIWIL1, PIWIL2 and PIWIL4), methylation of Piwi proteins being required for the interaction with Tudor domain-containing proteins and subsequent localization to the meiotic nuage. Methylates RPS10. Attenuates EGF signaling through the MAPK1/MAPK3 pathway acting at 2 levels. First, monomethylates EGFR; this enhances EGFR 'Tyr-1197' phosphorylation and PTPN6 recruitment, eventually leading to reduced SOS1 phosphorylation. Second, methylates RAF1 and probably BRAF, hence destabilizing these 2 signaling proteins and reducing their catalytic activity. Required for induction of E-selectin and VCAM-1, on the endothelial cells surface at sites of inflammation. Methylates HOXA9. Methylates and regulates SRGAP2 which is involved in cell migration and differentiation. Acts as a transcriptional corepressor in CRY1-mediated repression of the core circadian component PER1 by regulating the H4R3 dimethylation at the PER1 promoter. Publication Abstract from PubMed 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. Cryo-EM structure-based discovery of etravirine as a specific inhibitor of PRMT5/pICln protein-protein interaction for prostate cancer treatment.,Chi Z, Xu X, Shen Z, Deng X, Elzey BD, Li C, Jiang W, Hu CD J Enzyme Inhib Med Chem. 2026 Dec;41(1):2727844. doi: , 10.1080/14756366.2026.2727844. Epub 2026 Sep 8. PMID:42710907 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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