7u1m

Crystal structure of NTMT1 in complex with compound YD206

spinqualitylabelsall models 7u1m, resolution 3.17Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7u1m is a 2 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: X-ray diffraction, Resolution 3.17Å Ligands: KYF, SAH Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function NTM1A_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. Publication Abstract from PubMed Venglustat 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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