Probing the Plasticity in the Active Site of Protein N-terminal Methyltransferase 1 Using Bisubstrate Analogues

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Abstract
The bisubstrate analog strategy is a promising approach to develop potent and selective inhibitors for protein methyltransferases. Herein, the interactions of a series of bisubstrate analogs with protein N-terminal methyltransferase 1 (NTMT1) were examined to probe the molecular properties of the NTMT1 active site. Our results indicate that a 2-C to 4-C atom linker enables its respective bisubstrate analog to occupy both substrate and cofactor binding sites of NTMT1, but the bisubstrate analog 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 (Ki, app = 130 ± 40 pM) for NTMT1 to date, displaying over 3,000-fold selectivity over other methyltransferases and even to its homolog NTMT2. This study reveals the molecular basis for the plasticity of the NTMT1 active site. Additionally, our study outlines a general guidance on the development of bisubstrate inhibitors for any methyltransferases.
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Funding Information
  • National Cancer Institute (P30 CA023168)
  • National Institute of Allergy and Infectious Diseases (1R01AI127793)
  • National Institute of General Medical Sciences (1R01GM127896, R01GM117275)
  • Structural Genomics Consortium (1097737)
  • Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University

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