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PDBsum entry 2ort
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Oxidoreductase
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PDB id
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2ort
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Contents |
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* Residue conservation analysis
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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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Murine inducible nitric oxide synthase oxygenase domain (delta 114) 1- benzo[1,3]dioxol-5-ylmethyl-3s-(4-imidazol-1-yl-phenoxy)-piperidine complex
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Structure:
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Nitric oxide synthase, inducible. Chain: a. Fragment: oxygenase domain 114-498. Synonym: nos type ii, inducible no synthase, inducible nos, inos, macrophage nos, mac- nos. Engineered: yes
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Source:
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Mus musculus. House mouse. Organism_taxid: 10090. Gene: nos2, inosl. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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1.87Å
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R-factor:
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0.220
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R-free:
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0.240
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Authors:
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M.Adler,M.Whitlow
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Key ref:
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D.D.Davey
et al.
(2007).
Design, synthesis, and activity of 2-imidazol-1-ylpyrimidine derived inducible nitric oxide synthase dimerization inhibitors.
J Med Chem,
50,
1146-1157.
PubMed id:
DOI:
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Date:
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04-Feb-07
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Release date:
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17-Apr-07
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PROCHECK
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Headers
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References
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P29477
(NOS2_MOUSE) -
Nitric oxide synthase, inducible from Mus musculus
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Seq:
Struc:
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1144 a.a.
298 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
50:1146-1157
(2007)
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PubMed id:
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Design, synthesis, and activity of 2-imidazol-1-ylpyrimidine derived inducible nitric oxide synthase dimerization inhibitors.
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D.D.Davey,
M.Adler,
D.Arnaiz,
K.Eagen,
S.Erickson,
W.Guilford,
M.Kenrick,
M.M.Morrissey,
M.Ohlmeyer,
G.Pan,
V.M.Paradkar,
J.Parkinson,
M.Polokoff,
K.Saionz,
C.Santos,
B.Subramanyam,
R.Vergona,
R.G.Wei,
M.Whitlow,
B.Ye,
Z.S.Zhao,
J.J.Devlin,
G.Phillips.
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ABSTRACT
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By the screening of a combinatorial library for inhibitors of nitric oxide (NO)
formation by the inducible isoform of nitric oxide synthase (iNOS) using a
whole-cell assay, 2-(imidazol-1-yl)pyrimidines were identified. Compounds were
found to inhibit the dimerization of iNOS monomers, thus preventing the
formation of the dimeric, active form of the enzyme. Optimization led to the
selection of the potent, selective, and orally available iNOS dimerization
inhibitor, 21b, which significantly ameliorated adjuvant-induced arthritis in a
rat model. Analysis of the crystal structure of the 21b--iNOS monomer complex
provided a rationalization for both the SAR and the mechanism by which 21b
blocks the formation of the protein--protein interaction present in the dimeric
form of iNOS.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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G.H.Chu,
B.Le Bourdonnec,
M.Gu,
C.W.Ajello,
L.K.Leister,
I.Sellitto,
J.A.Cassel,
P.A.Tuthill,
H.O' Hare,
R.N.Dehaven,
and
R.E.Dolle
(2009).
Design and Synthesis of Imidazopyrimidine Derivatives as Potent iNOS Dimerization Inhibitors.
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Open Med Chem J,
3,
8.
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J.Fang,
and
R.B.Silverman
(2009).
A cellular model for screening neuronal nitric oxide synthase inhibitors.
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Anal Biochem,
390,
74-78.
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S.M.Francis,
A.Mittal,
M.Sharma,
and
P.V.Bharatam
(2008).
Design of benzene-1,2-diamines as selective inducible nitric oxide synthase inhibitors: a combined de novo design and docking analysis.
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J Mol Model,
14,
215-224.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
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Links
