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PDBsum entry 3jwz
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Oxidoreductase
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PDB id
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3jwz
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References listed in PDB file
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Key reference
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Title
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Unexpected binding modes of nitric oxide synthase inhibitors effective in the prevention of a cerebral palsy phenotype in an animal model.
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Authors
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S.L.Delker,
H.Ji,
H.Li,
J.Jamal,
J.Fang,
F.Xue,
R.B.Silverman,
T.L.Poulos.
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Ref.
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J Am Chem Soc, 2010,
132,
5437-5442.
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PubMed id
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Abstract
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Selective inhibition of the neuronal isoform of nitric oxide synthase NOS (nNOS)
has been shown to prevent brain injury and is important for the treatment of
various neurodegenerative disorders. However, given the high active site
conservation among all three NOS isoforms, the design of selective inhibitors is
an extremely challenging problem. Here we present the structural basis for why
novel and potent nNOS inhibitors exhibit the highest level of selectivity over
eNOS reported so far (approximately 3,800-fold). By using a combination of
crystallography, computational methods, and site-directed mutagenesis, we found
that inhibitor chirality and an unanticipated structural change of the target
enzyme control both the orientation and selectivity of these novel nNOS
inhibitors. A new hot spot generated as a result of enzyme elasticity provides
important information for the future fragment-based design of selective NOS
inhibitors.
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