6WJ7

The structure of NTMT1 in complex with compound C2A

Summary for 6WJ7

• Entry DOI: 10.2210/pdb6wj7/pdb
• Descriptor: N-terminal Xaa-Pro-Lys N-methyltransferase 1, GLY-PRO-LYS-ARG-ILE-ALA-NH2, 5'-{[(3S)-3-amino-3-carboxypropyl](ethyl)amino}-5'-deoxyadenosine, ... (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: 2
• Total formula weight: 28356.29

Authors

Srinivasan, K.,Chen, D.,Huang, R.,Noinaj, N. (deposition date: 2020-04-13, release date: 2020-08-19, Last modification date: 2024-04-24)

Primary citation

Chen, D.,Dong, C.,Dong, G.,Srinivasan, K.,Min, J.,Noinaj, N.,Huang, R.
Probing the Plasticity in the Active Site of Protein N-terminal Methyltransferase 1 Using Bisubstrate Analogues.
J.Med.Chem., 63:8419-8431, 2020

PubMed Abstract: The bisubstrate analogue strategy is a promising approach to develop potent and selective inhibitors for protein methyltransferases. Herein, the interactions of a series of bisubstrate analogues with protein N-terminal methyltransferase 1 (NTMT1) were examined to probe the molecular properties of the active site of NTMT1. Our results indicate that a 2-C to 4-C atom linker enables its respective bisubstrate analogue to occupy both substrate- and cofactor-binding sites of NTMT1, but the bisubstrate analogue with a 5-C atom linker only interacts with the substrate-binding site and functions as a substrate. Furthermore, the 4-C atom linker is the optimal and produces the most potent inhibitor ( = 130 ± 40 pM) for NTMT1 to date, displaying more than 3000-fold selectivity for other methyltransferases and even for its homologue NTMT2. This study reveals the molecular basis for the plasticity of the active site of NTMT1. Additionally, our study outlines general guidance on the development of bisubstrate inhibitors for any methyltransferases.

PubMed: 32605369
DOI: 10.1021/acs.jmedchem.0c00770

Experimental method

X-RAY DIFFRACTION (1.42 Å)