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PDBsum entry 4imt
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Oxidoreductase/oxidoreductase inhibitor
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PDB id
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4imt
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PDB id:
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| Name: |
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Oxidoreductase/oxidoreductase inhibitor
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Title:
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Structure of rat neuronal nitric oxide synthase in complex with 6,6'- ((4-(3-aminopropyl)-1,3-phenylene)bis(ethane-2,1-diyl))bis(4- methylpyridin-2-amine)
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Structure:
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Nitric oxide synthase, brain. Chain: a, b. Fragment: unp residues 297-718. Synonym: bnos, constitutive nos, nc-nos, nos type i, neuronal nos, n- nos, nnos, peptidyl-cysteine s-nitrosylase nos1. Engineered: yes
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Source:
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Rattus norvegicus. Rat. Organism_taxid: 10116. Gene: nos1, bnos. Expressed in: escherichia coli. Expression_system_taxid: 469008.
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Resolution:
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2.20Å
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R-factor:
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0.201
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R-free:
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0.248
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Authors:
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H.Li,T.L.Poulos
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Key ref:
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H.Huang
et al.
(2013).
Structure-guided design of selective inhibitors of neuronal nitric oxide synthase.
J Med Chem,
56,
3024-3032.
PubMed id:
DOI:
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Date:
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03-Jan-13
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Release date:
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24-Apr-13
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PROCHECK
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Headers
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References
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P29476
(NOS1_RAT) -
Nitric oxide synthase 1 from Rattus norvegicus
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Seq:
Struc:
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1429 a.a.
407 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.1.14.13.39
- nitric-oxide synthase (NADPH).
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Reaction:
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2 L-arginine + 3 NADPH + 4 O2 + H+ = 2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
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2
×
L-arginine
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+
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3
×
NADPH
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+
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4
×
O2
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+
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H(+)
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=
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2
×
L-citrulline
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+
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2
×
nitric oxide
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+
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3
×
NADP(+)
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+
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4
×
H2O
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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J Med Chem
56:3024-3032
(2013)
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PubMed id:
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Structure-guided design of selective inhibitors of neuronal nitric oxide synthase.
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H.Huang,
H.Li,
P.Martásek,
L.J.Roman,
T.L.Poulos,
R.B.Silverman.
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ABSTRACT
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Nitric oxide synthases (NOSs) comprise three closely related isoforms that
catalyze the oxidation of l-arginine to l-citrulline and the important second
messenger nitric oxide (NO). Pharmacological selective inhibition of neuronal
NOS (nNOS) has the potential to be therapeutically beneficial in various
neurodegenerative diseases. Here, we present a structure-guided, selective nNOS
inhibitor design based on the crystal structure of lead compound 1 in nNOS. The
best inhibitor, 7, exhibited low nanomolar inhibitory potency and good isoform
selectivities (nNOS over eNOS and iNOS are 472-fold and 239-fold, respectively).
Consistent with the good selectivity, 7 binds to nNOS and eNOS with different
binding modes. The distinctly different binding modes of 7, driven by the
critical residue Asp597 in nNOS, offers compelling insight to explain its
isozyme selectivity, which should guide future drug design programs.
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