6WH8

The structure of NTMT1 in complex with compound BM-30

Summary for 6WH8

• Entry DOI: 10.2210/pdb6wh8/pdb
• Related PRD ID: PRD_002315
• Descriptor: N-terminal Xaa-Pro-Lys N-methyltransferase 1, 4HP-PRO-LYS-ARG-NH2, BM-30, S-ADENOSYL-L-HOMOCYSTEINE, ... (4 entities in total)
• Functional Keywords: methyltransferase, enzyme, inhibitor complex, transferase, transferase-transferase inhibitor complex
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 56476.26

Authors

Noinaj, N.,Chen, D.,Huang, R. (deposition date: 2020-04-07, release date: 2020-08-26, Last modification date: 2024-10-23)

Primary citation

Mackie, B.D.,Chen, D.,Dong, G.,Dong, C.,Parker, H.,Schaner Tooley, C.E.,Noinaj, N.,Min, J.,Huang, R.
Selective Peptidomimetic Inhibitors of NTMT1/2: Rational Design, Synthesis, Characterization, and Crystallographic Studies.
J.Med.Chem., 63:9512-9522, 2020

PubMed Abstract: Protein N-terminal methyltransferases (NTMTs) methylate the α-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 (with a half-maximal inhibitory concentration of 0.89 ± 0.10 μM) is a competitive inhibitor to the peptide substrate and noncompetitive to the cofactor S-adenosylmethionine. 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 (IC 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.

PubMed: 32689795
DOI: 10.1021/acs.jmedchem.0c00689

Experimental method

X-RAY DIFFRACTION (1.729 Å)