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PDBsum entry 4k5e
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Oxidoreductase/oxidoreductase inhibitor
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PDB id
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4k5e
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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 neuronal nitric oxide synthase heme domain in complex with (r)-1,2-bis((2-amino-4-methylpyridin-6-yl)-methoxy)-propan-3- amine
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Structure:
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Nitric oxide synthase, brain. Chain: a, b. Fragment: heme domain (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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1.89Å
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R-factor:
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0.182
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R-free:
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0.212
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Authors:
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H.Li,T.L.Poulos
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Key ref:
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Q.Jing
et al.
(2013).
Chiral linkers to improve selectivity of double-headed neuronal nitric oxide synthase inhibitors.
Bioorg Med Chem Lett,
23,
5674-5679.
PubMed id:
DOI:
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Date:
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14-Apr-13
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Release date:
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18-Sep-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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*
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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Bioorg Med Chem Lett
23:5674-5679
(2013)
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PubMed id:
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Chiral linkers to improve selectivity of double-headed neuronal nitric oxide synthase inhibitors.
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Q.Jing,
H.Li,
G.Chreifi,
L.J.Roman,
P.Martásek,
T.L.Poulos,
R.B.Silverman.
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ABSTRACT
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To develop potent and selective nNOS inhibitors, new double-headed molecules
with chiral linkers that derive from natural amino acids or their derivatives
have been designed. The new structures contain two ether bonds, which greatly
simplifies the synthesis and accelerates structure optimization. Inhibitor
(R)-6b exhibits a potency of 32nM against nNOS and is 475 and 244 more selective
for nNOS over eNOS and iNOS, respectively. Crystal structures show that the
additional binding between the aminomethyl moiety of 6b and the two heme
propionates in nNOS, but not eNOS, is the structural basis for its high
selectivity. This work demonstrates the importance of stereochemistry in this
class of molecules, which significantly influences the potency and selectivity
of the inhibitors. The structure-activity information gathered here provides a
guide for future structure optimization.
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Links
