6chh
From Proteopedia
Structure of human NNMT in complex with bisubstrate inhibitor MS2756
Structural highlights
FunctionNNMT_HUMAN Catalyzes the N-methylation of nicotinamide and other pyridines to form pyridinium ions. This activity is important for biotransformation of many drugs and xenobiotic compounds. Publication Abstract from PubMedNicotinamide N-methyltransferase (NNMT) catalyzes the N-methylation of pyridine-containing compounds using the cofactor S-5'-adenosyl-L-methionine (SAM) as the methyl group donor. Through the regulation of the levels of its substrates, cofactor, and products, NNMT plays important role in physiology and pathophysiology. Overexpression of NNMT has been implicated in various human diseases. Potent and selective small-molecule NNMT inhibitors are valuable chemical tools for testing biological and therapeutic hypotheses. However, very few NNMT inhibitors have been reported. Here, we describe the discovery of a bisubstrate NNMT inhibitor MS2734 (6), and characterization of this inhibitor in biochemical, biophysical, kinetic, and structural studies. Importantly, we obtained the first crystal structure of human NNMT in complex with a small-molecule inhibitor. The structure of the NNMT-6 complex has unambiguously demonstrated that 6 occupied both substrate and cofactor binding sites. The findings paved the way for developing more potent and selective NNMT inhibitors in the future. Discovery of Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT).,Babault N, Allali-Hassani A, Li F, Fan J, Yue A, Ju K, Liu F, Vedadi M, Liu J, Jin J J Med Chem. 2018 Jan 10. doi: 10.1021/acs.jmedchem.7b01422. PMID:29320176[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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