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PDBsum entry 4ctr
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Oxidoreductase
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PDB id
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4ctr
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PDB id:
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| Name: |
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Oxidoreductase
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Title:
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Structure of rat neuronal nitric oxide synthase heme domain in complex with 2-(6-amino-4-methylpyridin-2-yl)-1-(3-(2-(6-amino-4- methylpyridin-2-yl)ethyl )phenyl)ethan-1-ol
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Structure:
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Nitric oxide synthase, brain. Chain: a, b. Fragment: heme domain, residues 297-718. Synonym: neuronal nitric oxide synthase, 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. Norway rat. Organism_taxid: 10116. 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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0.262
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Authors:
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H.Li,T.L.Poulos
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Key ref:
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S.Kang
et al.
(2014).
Nitric oxide synthase inhibitors that interact with both heme propionate and tetrahydrobiopterin show high isoform selectivity.
J Med Chem,
57,
4382-4396.
PubMed id:
DOI:
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Date:
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15-Mar-14
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Release date:
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07-May-14
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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.
408 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
57:4382-4396
(2014)
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PubMed id:
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Nitric oxide synthase inhibitors that interact with both heme propionate and tetrahydrobiopterin show high isoform selectivity.
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S.Kang,
W.Tang,
H.Li,
G.Chreifi,
P.Martásek,
L.J.Roman,
T.L.Poulos,
R.B.Silverman.
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ABSTRACT
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Overproduction of NO by nNOS is implicated in the pathogenesis of diverse
neuronal disorders. Since NO signaling is involved in diverse physiological
functions, selective inhibition of nNOS over other isoforms is essential to
minimize side effects. A series of α-amino functionalized aminopyridine
derivatives (3-8) were designed to probe the structure-activity relationship
between ligand, heme propionate, and H4B. Compound 8R was identified as the most
potent and selective molecule of this study, exhibiting a Ki of 24 nM for nNOS,
with 273-fold and 2822-fold selectivity against iNOS and eNOS, respectively.
Although crystal structures of 8R complexed with nNOS and eNOS revealed a
similar binding mode, the selectivity stems from the distinct electrostatic
environments in two isoforms that result in much lower inhibitor binding free
energy in nNOS than in eNOS. These findings provide a basis for further
development of simple, but even more selective and potent, nNOS inhibitors.
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Links
