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PDBsum entry 4uh6
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Oxidoreductase
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PDB id
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4uh6
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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 human nnos r354a g357d mutant heme domain in complex with 3-(2-(6-amino-4-methylpyridin-2-yl)ethyl)-5-(methyl(2-(methylamino) ethyl)amino)benzonitrile
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Structure:
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Nitric oxide synthase, brain. Chain: a, b. Synonym: constitutive nos, nc-nos, nos type i, neuronal nos, n-nos, nnos, peptidyl-cysteine s-nitrosylase nos1, bnos, neuronal nitric oxide synthase. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008.
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Resolution:
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1.98Å
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R-factor:
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0.175
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R-free:
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0.213
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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.
(2015).
2-Aminopyridines with a Truncated Side Chain To Improve Human Neuronal Nitric Oxide Synthase Inhibitory Potency and Selectivity.
J Med Chem,
58,
5548-5560.
PubMed id:
DOI:
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Date:
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23-Mar-15
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Release date:
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15-Jul-15
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PROCHECK
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Headers
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References
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P29475
(NOS1_HUMAN) -
Nitric oxide synthase 1 from Homo sapiens
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Seq:
Struc:
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1434 a.a.
413 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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*
PDB and UniProt seqs differ
at 2 residue positions (black
crosses)
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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
58:5548-5560
(2015)
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PubMed id:
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2-Aminopyridines with a Truncated Side Chain To Improve Human Neuronal Nitric Oxide Synthase Inhibitory Potency and Selectivity.
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S.Kang,
H.Li,
W.Tang,
P.Martásek,
L.J.Roman,
T.L.Poulos,
R.B.Silverman.
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ABSTRACT
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We have analyzed a recently obtained crystal structure of human neuronal nitric
oxide synthase (nNOS) and then designed and synthesized several 2-aminopyridine
derivatives containing a truncated side chain to avoid the hydrophobic pocket
that differentiates human and rat nNOS in an attempt to explore alternative
binding poses along the substrate access channel of human nNOS. Introduction of
an N-methylethane-1,2-diamine side chain and conformational constraints such as
benzonitrile and pyridine as the middle aromatic linker were sufficient to
increase human and rat nNOS binding affinity and inducible and endothelial NOS
selectivity. We found that 14b is a potent inhibitor; the binding modes with
human and rat nNOS are unexpected, inducing side chain rotamer changes in Gln478
(rat) at the top of the active site. Compound 19c exhibits Ki values of 24 and
55 nM for rat and human nNOS, respectively, with 153-fold iNOS and 1040-fold
eNOS selectivity. 19c has 18% oral bioavailability.
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Links
