6PVS

Structure of Nicotinamide N-Methyltransferase (NNMT) in complex with inhibitor LL320

6PVS の概要

• エントリーDOI: 10.2210/pdb6pvs/pdb
• 分子名称: NNMT protein, 9-(5-{[(3R)-3-amino-3-carboxypropyl][3-(3-carbamoylphenyl)prop-2-yn-1-yl]amino}-5-deoxy-alpha-D-lyxofuranosyl)-9H-purin-6-amine (3 entities in total)
• 機能のキーワード: methyltransferase, inhibitor, 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: 127962.25

構造登録者

Noinaj, N.,Huang, R.,Chen, D.,Yadav, R. (登録日: 2019-07-21, 公開日: 2019-11-27, 最終更新日: 2024-03-13)

主引用文献

Chen, D.,Li, L.,Diaz, K.,Iyamu, I.D.,Yadav, R.,Noinaj, N.,Huang, R.
Novel Propargyl-Linked Bisubstrate Analogues as Tight-Binding Inhibitors for NicotinamideN-Methyltransferase.
J.Med.Chem., 62:10783-10797, 2019

PubMed Abstract: Nicotinamide -methyltransferase (NNMT) catalyzes the methyl transfer from the cofactor -adenosylmethionine to nicotinamide and other pyridine-containing compounds. NNMT is an important regulator for nicotinamide metabolism and methylation potential. Aberrant expression levels of NNMT have been implicated in cancer, metabolic, and neurodegenerative diseases, which makes NNMT a potential therapeutic target. Therefore, potent and selective NNMT inhibitors can serve as valuable tools to investigate the roles of NNMT in its mediated diseases. Here, we applied a rational strategy to design and synthesize the tight-binding bisubstrate inhibitor LL320 through a novel propargyl linker. LL320 demonstrates a value of 1.6 ± 0.3 nM, which is the most potent inhibitor to date. The cocrystal structure of LL320 confirms its interaction with both the substrate and cofactor binding sites on NNMT. Importantly, this is the first example of using the propargyl linker to construct potent methyltransferase inhibitors, which will expand our understanding of the transition state of methyl transfer.

PubMed: 31724854
DOI: 10.1021/acs.jmedchem.9b01255

実験手法

X-RAY DIFFRACTION (2.575 Å)