6ORR

Co-crystal structure of human NicotinamideN-Methyltransferase (NNMT) in complex with High-Affinity Alkynyl Bisubstrate Inhibitor NS1

6ORR の概要

• エントリーDOI: 10.2210/pdb6orr/pdb
• 分子名称: NNMT protein, 9-{9-amino-6-[(3-carbamoylphenyl)ethynyl]-5,6,7,8,9-pentadeoxy-D-glycero-alpha-L-talo-decofuranuronosyl}-9H-purin-6-amine, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: methyltransferase nicotinamide, alkynyl bisubstrate inhibitor, alkyne linker methyltransferase inhibitor, high-affinity alkynyl nucleoside, sam slow-binding inhibition, tight-binding inhibition, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 128362.66

構造登録者

May, E.J.,Policarpo, R.L.,Gaudet, R. (登録日: 2019-04-30, 公開日: 2019-10-23, 最終更新日: 2023-10-11)

主引用文献

Policarpo, R.L.,Decultot, L.,May, E.,Kuzmic, P.,Carlson, S.,Huang, D.,Chu, V.,Wright, B.A.,Dhakshinamoorthy, S.,Kannt, A.,Rani, S.,Dittakavi, S.,Panarese, J.D.,Gaudet, R.,Shair, M.D.
High-Affinity Alkynyl Bisubstrate Inhibitors of NicotinamideN-Methyltransferase (NNMT).
J.Med.Chem., 62:9837-9873, 2019

PubMed Abstract: Nicotinamide -methyltransferase (NNMT) is a metabolic enzyme that methylates nicotinamide (NAM) using cofactor -adenosylmethionine (SAM). NNMT overexpression has been linked to diabetes, obesity, and various cancers. In this work, structure-based rational design led to the development of potent and selective alkynyl bisubstrate inhibitors of NNMT. The reported nicotinamide-SAM conjugate (named NS1) features an alkyne as a key design element that closely mimics the linear, 180° transition state geometry found in the NNMT-catalyzed SAM → NAM methyl transfer reaction. NS1 was synthesized in 14 steps and found to be a high-affinity, subnanomolar NNMT inhibitor. An X-ray cocrystal structure and SAR study revealed the ability of an alkynyl linker to span the methyl transfer tunnel of NNMT with ideal shape complementarity. The compounds reported in this work represent the most potent and selective NNMT inhibitors reported to date. The rational design principle described herein could potentially be extended to other methyltransferase enzymes.

PubMed: 31589440
DOI: 10.1021/acs.jmedchem.9b01238

実験手法

X-RAY DIFFRACTION (2.25 Å)