6V0O

PRMT5 bound to the PBM peptide from pICln

Summary for 6V0O

• Entry DOI: 10.2210/pdb6v0o/pdb
• Descriptor: Protein arginine N-methyltransferase 5, Methylosome protein 50, PBM peptide, ... (5 entities in total)
• Functional Keywords: methylation, methyltransferase, epigenetic, sdma, splicing, transferase-splicing complex, transferase/splicing
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 111319.68

Authors

McMillan, B.J.,Raymond, D.D. (deposition date: 2019-11-19, release date: 2020-08-26, Last modification date: 2023-10-11)

Primary citation

Mulvaney, K.M.,Blomquist, C.,Acharya, N.,Li, R.,Ranaghan, M.J.,O'Keefe, M.,Rodriguez, D.J.,Young, M.J.,Kesar, D.,Pal, D.,Stokes, M.,Nelson, A.J.,Jain, S.S.,Yang, A.,Mullin-Bernstein, Z.,Columbus, J.,Bozal, F.K.,Skepner, A.,Raymond, D.,LaRussa, S.,McKinney, D.C.,Freyzon, Y.,Baidi, Y.,Porter, D.,Aguirre, A.J.,Ianari, A.,McMillan, B.,Sellers, W.R.
Molecular basis for substrate recruitment to the PRMT5 methylosome.
Mol.Cell, 81:3481-, 2021

PubMed Abstract: PRMT5 is an essential arginine methyltransferase and a therapeutic target in MTAP-null cancers. PRMT5 uses adaptor proteins for substrate recruitment through a previously undefined mechanism. Here, we identify an evolutionarily conserved peptide sequence shared among the three known substrate adaptors (CLNS1A, RIOK1, and COPR5) and show that it is necessary and sufficient for interaction with PRMT5. We demonstrate that PRMT5 uses modular adaptor proteins containing a common binding motif for substrate recruitment, comparable with other enzyme classes such as kinases and E3 ligases. We structurally resolve the interface with PRMT5 and show via genetic perturbation that it is required for methylation of adaptor-recruited substrates including the spliceosome, histones, and ribosomal complexes. Furthermore, disruption of this site affects Sm spliceosome activity, leading to intron retention. Genetic disruption of the PRMT5-substrate adaptor interface impairs growth of MTAP-null tumor cells and is thus a site for development of therapeutic inhibitors of PRMT5.

PubMed: 34358446
DOI: 10.1016/j.molcel.2021.07.019

Experimental method

X-RAY DIFFRACTION (2.86 Å)