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PDBsum entry 6pp2
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Oxidoreductase/inhibitor
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PDB id
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6pp2
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PDB id:
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| Name: |
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Oxidoreductase/inhibitor
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Title:
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Structure of human endothelial nitric oxide synthase heme domain in complex with 4-((4-(2-amino-4-methylquinolin-7-yl)-2-(aminomethyl) phenoxy)methyl)benzonitrile
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Structure:
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Nitric oxide synthase, endothelial. Chain: a, b, c, d. Synonym: constitutive nos,cnos,ec-nos,endothelial nos,enos,nos type iii,nosiii. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Cell: endothelial. Gene: nos3. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
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Resolution:
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2.02Å
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R-factor:
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0.201
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R-free:
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0.246
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Authors:
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G.Chreifi,H.Li,T.L.Poulos
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Key ref:
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M.A.Cinelli
et al.
(2020).
First Contact: 7-Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate.
J Med Chem,
63,
4528-4554.
PubMed id:
DOI:
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Date:
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05-Jul-19
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Release date:
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29-Apr-20
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PROCHECK
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Headers
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References
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P29474
(NOS3_HUMAN) -
Nitric oxide synthase 3 from Homo sapiens
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Seq:
Struc:
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1203 a.a.
404 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
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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
63:4528-4554
(2020)
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PubMed id:
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First Contact: 7-Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate.
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M.A.Cinelli,
C.T.Reidl,
H.Li,
G.Chreifi,
T.L.Poulos,
R.B.Silverman.
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ABSTRACT
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Inhibition of neuronal nitric oxide synthase (nNOS), an enzyme implicated in
neurodegenerative disorders, is an attractive strategy for treating or
preventing these diseases. We previously developed several classes of
2-aminoquinoline-based nNOS inhibitors, but these compounds had drawbacks
including off-target promiscuity, low activity against human nNOS, and only
modest selectivity for nNOS over related enzymes. In this study, we synthesized
new nNOS inhibitors based on 7-phenyl-2-aminoquinoline and assayed them against
rat and human nNOS, human eNOS, and murine and (in some cases) human iNOS.
Compounds with a meta-relationship between the aminoquinoline and a
positively charged tail moiety were potent and had up to nearly 900-fold
selectivity for human nNOS over human eNOS. X-ray crystallography indicates that
the amino groups of some compounds occupy a water-filled pocket surrounding an
nNOS-specific aspartate residue (absent in eNOS). This interaction was confirmed
by mutagenesis studies, making 7-phenyl-2-aminoquinolines the first
aminoquinolines to interact with this residue.
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Links
