7u1m | pdb_00007u1m
Crystal structure of NTMT1 in complex with compound YD206
Structural highlights
FunctionNTM1A_HUMAN Distributive alpha-N-methyltransferase that methylates the N-terminus of target proteins containing the N-terminal motif [Ala/Pro/Ser]-Pro-Lys when the initiator Met is cleaved. Specifically catalyzes mono-, di- or tri-methylation of exposed alpha-amino group of Ala or Ser residue in the [Ala/Ser]-Pro-Lys motif and mono- or di-methylation of Pro in the Pro-Pro-Lys motif. Some of the substrates may be primed by METTL11B-mediated monomethylation. Responsible for the N-terminal methylation of KLHL31, MYL2, MYL3, RB1, RCC1, RPL23A and SET. Required during mitosis for normal bipolar spindle formation and chromosome segregation via its action on RCC1.[1] [2] [3] Publication Abstract from PubMedVenglustat is a known allosteric inhibitor for ceramide glycosyltransferase, investigated in diseases caused by lysosomal dysfunction. Here, we identified venglustat as a potent inhibitor (IC(50) = 0.42 muM) of protein N-terminal methyltransferase 1 (NTMT1) by screening 58,130 compounds. Furthermore, venglustat exhibited selectivity for NTMT1 over 36 other methyltransferases. The crystal structure of NTMT1-venglustat and inhibition mechanism revealed that venglustat competitively binds at the peptide substrate site. Meanwhile, venglustat potently inhibited protein N-terminal methylation levels in cells (IC(50) = 0.5 muM). Preliminary structure-activity relationships indicated that the quinuclidine and fluorophenyl parts of venglustat are important for NTMT1 inhibition. In summary, we confirmed that venglustat is a bona fide NTMT1 inhibitor, which would advance the study on the biological roles of NTMT1. Additionally, this is the first disclosure of NTMT1 as a new molecular target of venglustat, which would cast light on its mechanism of action to guide the clinical investigations. Venglustat Inhibits Protein N-Terminal Methyltransferase 1 in a Substrate-Competitive Manner.,Dong G, Deng Y, Yasgar A, Yadav R, Talley D, Zakharov AV, Jain S, Rai G, Noinaj N, Simeonov A, Huang R J Med Chem. 2022 Sep 22;65(18):12334-12345. doi: 10.1021/acs.jmedchem.2c01050. , Epub 2022 Sep 8. PMID:36074125[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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