 |
PDBsum entry 6pnh
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Oxidoreductase/inhibitor
|
PDB id
|
|
|
|
6pnh
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
PDB id:
|
|
|
|
| Name: |
|
Oxidoreductase/inhibitor
|
|
|
Title:
|
|
Structure of human neuronal nitric oxide synthase r354a/g357d mutant heme domain in complex with 7-(3-(aminomethyl)-4-isopropoxyphenyl)-4- methylquinolin-2-amine
|
|
Structure:
|
|
Nitric oxide synthase, brain. Chain: a, b. Synonym: constitutive nos,nc-nos,nos type i,neuronal nos,nnos, peptidyl-cysteine s-nitrosylase nos1,bnos. Engineered: yes. Mutation: yes
|
|
Source:
|
|
Homo sapiens. Human. Organism_taxid: 9606. Organ: brain. Gene: nos1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
|
|
Resolution:
|
|
|
1.85Å
|
R-factor:
|
0.204
|
R-free:
|
0.246
|
|
|
Authors:
|
|
H.Li,T.L.Poulos
|
|
Key ref:
|
|
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:
|
|
|
Date:
|
|
|
02-Jul-19
|
Release date:
|
29-Apr-20
|
|
|
|
|
|
|
PROCHECK
|
|
|
|
|
|
Headers
|
|
|
|
References
|
|
|
|
|
|
|
|
P29475
(NOS1_HUMAN) -
Nitric oxide synthase 1 from Homo sapiens
|
|
|
|
Seq:
Struc:
|
|
|
|
1434 a.a.
412 a.a.*
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Key: |
 |
PfamA domain |
|
|
 |
Secondary structure |
|
|
*
PDB and UniProt seqs differ
at 2 residue positions (black
crosses)
|
|
|
|
|
|
|
|
|
|
|
|
|
Enzyme class:
|
|
E.C.1.14.13.39
- nitric-oxide synthase (NADPH).
|
|
|
|
|
|
|
Reaction:
|
|
2 L-arginine + 3 NADPH + 4 O2 + H+ = 2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
|
|
|
|
|
|
2
×
L-arginine
|
+
|
3
×
NADPH
|
+
|
4
×
O2
|
+
|
H(+)
|
=
|
2
×
L-citrulline
|
+
|
2
×
nitric oxide
|
+
|
3
×
NADP(+)
|
+
|
4
×
H2O
|
|
|
|
|
|
|
|
|
|
|
|
|
Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
|
| |
|
DOI no:
|
J Med Chem
63:4528-4554
(2020)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
First Contact: 7-Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate.
|
|
M.A.Cinelli,
C.T.Reidl,
H.Li,
G.Chreifi,
T.L.Poulos,
R.B.Silverman.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
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.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Links
