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PDBsum entry 1vaf
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Oxidoreductase
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PDB id
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1vaf
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structures of nitric oxide synthase isoforms complexed with the inhibitor ar-R17477 suggest a rational basis for specificity and inhibitor design.
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Authors
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R.Fedorov,
R.Vasan,
D.K.Ghosh,
I.Schlichting.
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Ref.
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Proc Natl Acad Sci U S A, 2004,
101,
5892-5897.
[DOI no: ]
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PubMed id
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Abstract
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The high level of amino acid conservation and structural similarity of the
substrate-binding sites of the oxygenase domains of the nitric oxide synthase
(NOS) isoforms (eNOSoxy, iNOSoxy, nNOSoxy) make the interpretation of the
structural basis of inhibitor isoform specificity a challenge, and provide few
clues for the design of new selective compounds. Crystal structures of iNOSoxy
and nNOSoxy complexed with the neuronal NOS-specific inhibitor AR-R17447 suggest
that specificity is provided by the interaction of the chlorophenyl group with
an isoform-unique substrate access channel residue (L337 in rat neuronal NOS,
N115 in mouse inducible NOS). This is confirmed by biochemical analysis of
site-directed mutants. Inhibitors combining guanidinium-like structural motifs
with long chains specifically targeting this residue are good candidates for
rational isoform-specific drug design. Based on this finding, modifications of
AR-R17447 to improve the specificity for the human isoforms are suggested.
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Figure 1.
Fig. 1. F[obs] - F[calc] electron density omit maps
contoured at 3  superimposed with the
final model of the inhibitor AR-R17477 bound to nNOSoxy and the
two crystallographically independent molecules in the asymmetric
unit of iNOSoxy crystals (mol.1 and mol.2).
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Figure 2.
Fig. 2. Schematic representation of the interactions of
AR-R17477 and nNOSoxy and iNOSoxy (two molecules in asymmetric
unit, two conformations each). Dashed lines correspond to
hydrogen bonds, dotted lines correspond to van der Waals
interactions.
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