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PDBsum entry 6chh
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Transferase/transferase inhibitor
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PDB id
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6chh
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References listed in PDB file
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Key reference
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Title
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Discovery of bisubstrate inhibitors of nicotinamide n-Methyltransferase (nnmt).
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Authors
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N.Babault,
A.Allali-Hassani,
F.Li,
J.Fan,
A.Yue,
K.Ju,
F.Liu,
M.Vedadi,
J.Liu,
J.Jin.
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Ref.
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J Med Chem, 2018,
61,
1541-1551.
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PubMed id
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Abstract
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Nicotinamide 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 an 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.
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