6PVS

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

Summary for 6PVS

• Entry DOI: 10.2210/pdb6pvs/pdb
• Descriptor: 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)
• Functional Keywords: methyltransferase, inhibitor, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 127962.25

Authors

Noinaj, N.,Huang, R.,Chen, D.,Yadav, R. (deposition date: 2019-07-21, release date: 2019-11-27, Last modification date: 2024-03-13)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.575 Å)