6wh8

The structure of NTMT1 in complex with compound BM-30

spinqualitylabelsall models 6wh8, resolution 1.73Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6wh8 is a 4 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.729Å Ligands: 4HP, NH2, 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 Protein N-terminal methyltransferases (NTMTs) methylate the alpha-N-terminal amines of proteins starting with the canonical X-P-K/R motif. Genetic studies imply that NTMT1 regulates cell mitosis and DNA damage repair. Herein, we report the rational design and development of the first potent peptidomimetic inhibitor for NTMT1/2. Biochemical and cocrystallization studies manifest that BM30 (with a half-maximal inhibitory concentration of 0.89 +/- 0.10 muM) is a competitive inhibitor to the peptide substrate and noncompetitive to the cofactor S-adenosylmethionine. BM30 exhibits over 100-fold selectivity to NTMT1/2 among a panel of 41 MTs, indicating its potential to achieve high selectivity when targeting the peptide substrate binding site of NTMT1/2. Its cell-permeable analogue DC432 (IC(50) of 54 +/- 4 nM) decreases the N-terminal methylation level of the regulator of chromosome condensation 1 and SET proteins in HCT116 cells. This proof-of principle study provides valuable probes for NTMT1/2 and highlights the opportunity to develop more cell-potent inhibitors to elucidate the function of NTMTs in the future. Selective Peptidomimetic Inhibitors of NTMT1/2: Rational Design, Synthesis, Characterization, and Crystallographic Studies.,Mackie BD, Chen D, Dong G, Dong C, Parker H, Schaner Tooley CE, Noinaj N, Min J, Huang R J Med Chem. 2020 Sep 10;63(17):9512-9522. doi: 10.1021/acs.jmedchem.0c00689. Epub , 2020 Aug 5. PMID:32689795 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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