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PDBsum entry 1mmw

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protein ligands metals Protein-protein interface(s) links
Oxidoreductase PDB id
1mmw
Jmol
Contents
Protein chains
407 a.a. *
Ligands
ACT ×2
HEM ×2
H4B ×2
VIO ×2
Metals
_ZN
Waters ×459
* Residue conservation analysis
PDB id:
1mmw
Name: Oxidoreductase
Title: Rat neuronal nos heme domain with vinyl-l-nio bound
Structure: Nitric-oxide synthase, brain. Chain: a, b. Fragment: heme domain. Synonym: nos, type i. Neuronal nos. N-nos. Nnos. Constituti nc-nos. Bnos. Nitric oxidase synthase. Engineered: yes
Source: Rattus norvegicus. Norway rat. Organism_taxid: 10116. Organ: brain. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Biol. unit: Dimer (from PQS)
Resolution:
2.00Å     R-factor:   0.231     R-free:   0.266
Authors: L.E.Bretscher,H.Li,T.L.Poulos,O.W.Griffith
Key ref:
L.E.Bretscher et al. (2003). Structural characterization and kinetics of nitric-oxide synthase inhibition by novel N5-(iminoalkyl)- and N5-(iminoalkenyl)-ornithines. J Biol Chem, 278, 46789-46797. PubMed id: 12960153 DOI: 10.1074/jbc.M306787200
Date:
04-Sep-02     Release date:   16-Sep-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P29476  (NOS1_RAT) -  Nitric oxide synthase, brain
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1429 a.a.
407 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.1.14.13.39  - Nitric-oxide synthase (Nadph dependent).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: 2 L-arginine + 3 NADPH + 4 O2 = 2 L-citrulline + 2 nitric oxide + 3 NADP+ + 4 H2O
2 × L-arginine
Bound ligand (Het Group name = VIO)
matches with 73.00% similarity
+ 3 × NADPH
+ 4 × O(2)
= 2 × L-citrulline
+ 2 × nitric oxide
+ 3 × NADP(+)
+ 4 × H(2)O
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     oxidation-reduction process   2 terms 
  Biochemical function     nitric-oxide synthase activity     2 terms  

 

 
    reference    
 
 
DOI no: 10.1074/jbc.M306787200 J Biol Chem 278:46789-46797 (2003)
PubMed id: 12960153  
 
 
Structural characterization and kinetics of nitric-oxide synthase inhibition by novel N5-(iminoalkyl)- and N5-(iminoalkenyl)-ornithines.
L.E.Bretscher, H.Li, T.L.Poulos, O.W.Griffith.
 
  ABSTRACT  
 
Isoform-specific nitric-oxide synthase (NOS) inhibitors may prove clinically useful in reducing the pathophysiological effects associated with increased neuronal NOS (nNOS) or inducible NOS (iNOS) activity in a variety of neurological and inflammatory disorders. Analogs of the NOS substrate L-arginine are pharmacologically attractive inhibitors because of their stability, reliable cell uptake, and good selectivity for NOS over other heme proteins. Some inhibitory arginine analogs show significant isoform selectivity although the structural or mechanistic basis of such selectivity is generally poorly understood. In the present studies, we determined by x-ray crystallography the binding interactions between rat nNOS and N5-(1-imino-3-butenyl)-L-ornithine (L-VNIO), a previously identified mechanism-based, irreversible inactivator with moderate nNOS selectivity. We have also synthesized and mechanistically characterized several L-VNIO analogs and find, surprisingly, that even relatively minor structural changes produce inhibitors that are either iNOS-selective or non-selective. Furthermore, derivatives having a methyl group added to the butenyl moiety of L-VNIO and L-VNIO derivatives that are analogs of homoarginine rather than arginine display slow-on, slow-off kinetics rather than irreversible inactivation. These results elucidate some of the structural requirements for isoform-selective inhibition by L-VNIO and its related alkyl- and alkenyl-imino ornithine and lysine derivatives and may provide information useful in the ongoing rational design of isoform-selective inhibitors.
 
  Selected figure(s)  
 
Figure 1.
FIG. 1. Structures of the NOS substrates L-arginine and L-homoarginine, the known nNOS-selective inhibitor, L-VNIO, and novel NOS inhibiting L-VNIO derivatives described in this work.
Figure 3.
FIG. 3. Crystal structure of L-VNIO bound to the active site of the rat nNOS oxygenase domain. Dashed lines indicate hydrogen bonds. For clarity, only the side chains of the labeled residues are shown. The atom color schemes are: carbon, gray; oxygen, red; nitrogen, blue.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 46789-46797) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20979083 M.Lluis, Y.Wang, A.F.Monzingo, W.Fast, and J.D.Robertus (2011).
Characterization of C-alkyl amidines as bioavailable covalent reversible inhibitors of human DDAH-1.
  ChemMedChem, 6, 81-88.
PDB codes: 3p8e 3p8p
19663506 Y.Wang, A.F.Monzingo, S.Hu, T.H.Schaller, J.D.Robertus, and W.Fast (2009).
Developing dual and specific inhibitors of dimethylarginine dimethylaminohydrolase-1 and nitric oxide synthase: toward a targeted polypharmacology to control nitric oxide.
  Biochemistry, 48, 8624-8635.
PDB codes: 3i2e 3i4a
16101283 J.Madeo, and M.R.Gunner (2005).
Modeling binding kinetics at the Q(A) site in bacterial reaction centers.
  Biochemistry, 44, 10994-11004.  
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. Where a reference describes a PDB structure, the PDB codes are shown on the right.