9mgm
Crystal structure of PRMT5:MEP50 in complex with MTA and compound 24
Structural highlights
FunctionMEP50_HUMAN Non-catalytic component of the 20S PRMT5-containing methyltransferase complex, which modifies specific arginines to dimethylarginines in several spliceosomal Sm proteins and histones. This modification targets Sm proteins to the survival of motor neurons (SMN) complex for assembly into small nuclear ribonucleoprotein core particles. Might play a role in transcription regulation. The 20S PRMT5-containing methyltransferase complex also 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.[1] [2] Publication Abstract from PubMedDeletion of the MTAP gene leads to accumulation of the substrate of the MTAP protein, methylthioadenosine (MTA). MTA binds PRMT5 competitively with S-adenosyl-l-methionine (SAM), and selective inhibition of the PRMT5*MTA complex relative to the PRMT5*SAM complex can lead to selective killing of cancer cells with MTAP deletion. Herein, we describe the discovery of novel compounds using structure-based drug design to switch the mechanism of binding of known, SAM-cooperative PRMT5 inhibitors to an MTA-cooperative binding mechanism by occupying the portion of the SAM binding pocket in PRMT5 that is unoccupied when MTA is bound and hydrogen bonding to Arg368, thereby allowing them to selectively target MTAP-deleted cancer cells. MTA-Cooperative PRMT5 Inhibitors: Mechanism Switching Through Structure-Based Design.,Cottrell KM, Whittington DA, Briggs KJ, Jahic H, Ali JA, Amor AJ, Gotur D, Tonini MR, Zhang W, Huang A, Maxwell JP J Med Chem. 2025 Feb 27;68(4):4217-4236. doi: 10.1021/acs.jmedchem.4c01998. Epub , 2025 Feb 7. PMID:39919252[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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