7EI2

Structure of human NNMT in complex with macrocyclic peptide 8

Summary for 7EI2

• Entry DOI: 10.2210/pdb7ei2/pdb
• Descriptor: Nicotinamide N-methyltransferase, macrocyclic peptide 8 (3 entities in total)
• Functional Keywords: nicotinamide n-methyltransferase, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 30066.54

Authors

Hayashi, K.,Mikamiyama, H.,Uehara, S.,Yamamoto, S.,Cary, D.,Nishikawa, J.,Ueda, T.,Ozasa, H.,Mihara, K.,Yoshimura, N.,Kawai, T.,Ono, T.,Yamamoto, S.,Fumoto, M. (deposition date: 2021-03-30, release date: 2022-03-30, Last modification date: 2023-11-29)

Primary citation

Hayashi, K.,Uehara, S.,Yamamoto, S.,Cary, D.R.,Nishikawa, J.,Ueda, T.,Ozasa, H.,Mihara, K.,Yoshimura, N.,Kawai, T.,Ono, T.,Yamamoto, S.,Fumoto, M.,Mikamiyama, H.
Macrocyclic Peptides as a Novel Class of NNMT Inhibitors: A SAR Study Aimed at Inhibitory Activity in the Cell.
Acs Med.Chem.Lett., 12:1093-1101, 2021

PubMed Abstract: Nicotinamide -methyltransferase (NNMT), which catalyzes the methylation of nicotinamide, is a cytosolic enzyme that has attracted much attention as a therapeutic target for a variety of diseases. However, despite the considerable interest in this target, reports of NNMT inhibitors have still been limited to date. In this work, utilizing translated macrocyclic peptide libraries, we identified peptide as a novel class of NNMT inhibitors. Further exploration based on the X-ray cocrystal structures of the peptides with NNMT provided a dramatic improvement in inhibitory activity (peptide : IC = 0.15 nM). Furthermore, by balance of the peptides' lipophilicity and biological activity, inhibitory activity against NNMT in cell-based assay was successfully achieved (peptide : cell-based IC = 770 nM). These findings illuminate the potential of cyclic peptides as a relatively new drug discovery modality even for intracellular targets.

PubMed: 34267879
DOI: 10.1021/acsmedchemlett.1c00134

Experimental method

X-RAY DIFFRACTION (2.08 Å)