7EGU

Structure of human NNMT in complex with macrocyclic peptide X

7EGU の概要

• エントリーDOI: 10.2210/pdb7egu/pdb
• 分子名称: Nicotinamide N-methyltransferase, macrocyclic peptide X (3 entities in total)
• 機能のキーワード: nicotinamide n-methyltransferase, transferase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 30228.80

構造登録者

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. (登録日: 2021-03-26, 公開日: 2021-12-15, 最終更新日: 2023-11-29)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.9 Å)