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PDBsum entry 6pvs
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Transferase/transferase inhibitor
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PDB id
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6pvs
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References listed in PDB file
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Key reference
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Title
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Novel propargyl-Linked bisubstrate analogues as tight-Binding inhibitors for nicotinamide n-Methyltransferase.
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Authors
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D.Chen,
L.Li,
K.Diaz,
I.D.Iyamu,
R.Yadav,
N.Noinaj,
R.Huang.
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Ref.
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J Med Chem, 2019,
62,
10783-10797.
[DOI no: ]
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PubMed id
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Abstract
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Nicotinamide N-methyltransferase (NNMT) catalyzes the methyl transfer
from the cofactor S-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 Ki 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.
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