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PDBsum entry 3eah
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Oxidoreductase
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PDB id
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3eah
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References listed in PDB file
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Key reference
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Title
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Anchored plasticity opens doors for selective inhibitor design in nitric oxide synthase.
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Authors
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E.D.Garcin,
A.S.Arvai,
R.J.Rosenfeld,
M.D.Kroeger,
B.R.Crane,
G.Andersson,
G.Andrews,
P.J.Hamley,
P.R.Mallinder,
D.J.Nicholls,
S.A.St-Gallay,
A.C.Tinker,
N.P.Gensmantel,
A.Mete,
D.R.Cheshire,
S.Connolly,
D.J.Stuehr,
A.Aberg,
A.V.Wallace,
J.A.Tainer,
E.D.Getzoff.
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Ref.
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Nat Chem Biol, 2008,
4,
700-707.
[DOI no: ]
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PubMed id
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Abstract
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Nitric oxide synthase (NOS) enzymes synthesize nitric oxide, a signal for
vasodilatation and neurotransmission at low concentrations and a defensive
cytotoxin at higher concentrations. The high active site conservation among all
three NOS isozymes hinders the design of selective NOS inhibitors to treat
inflammation, arthritis, stroke, septic shock and cancer. Our crystal structures
and mutagenesis results identified an isozyme-specific induced-fit binding mode
linking a cascade of conformational changes to a new specificity pocket.
Plasticity of an isozyme-specific triad of distant second- and third-shell
residues modulates conformational changes of invariant first-shell residues to
determine inhibitor selectivity. To design potent and selective NOS inhibitors,
we developed the anchored plasticity approach: anchor an inhibitor core in a
conserved binding pocket, then extend rigid bulky substituents toward remote
specificity pockets, which become accessible upon conformational changes of
flexible residues. This approach exemplifies general principles for the design
of selective enzyme inhibitors that overcome strong active site conservation.
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Figure 3.
(a) Solvent-accessible surfaces for the iNOS (left) and eNOS
(right) active sites colored according to Figure 2. The core of
compound 9 binds closer and more parallel to the heme in eNOS.
In iNOS, side chain rotations of Gln, Arg and Arg388 open the
Gln specificity pocket for binding of the bulky inhibitor tail.
(b) Stereoview of the superimposition of bovine eNOS–compound
9 (yellow) and human iNOS–compound 9 (blue) X-ray structures,
highlighting the cascade of conformational changes of
first-shell and second-shell residues upon inhibitor binding to
iNOS.
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Figure 5.
Moderately selective compound 16 binds to mouse iNOSox
similarly to bulky quinazoline and aminopyridine inhibitors and
induces the Gln-open conformation. Residues are colored
according to Figure 2. The F[o] – F[c] electron density map
contoured at 3  (blue
mesh) is shown around the inhibitor (pink).
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Chem Biol
(2008,
4,
700-707)
copyright 2008.
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