spacer
spacer

PDBsum entry 1vaf
Go to PDB code: 
protein ligands metals Protein-protein interface(s) links
Oxidoreductase PDB id
1vaf

 

 

 

 

Loading ...

 
JSmol PyMol  
Contents
Protein chains
419 a.a. *
Ligands
HEM ×2
H4B ×2
ARR ×2
Metals
_ZN ×2
Waters ×181
* Residue conservation analysis
PDB id:
1vaf
Name: Oxidoreductase
Title: Inducible nitric oxide synthase oxygenase domain complexed with the inhibitor ar-r17477
Structure: Nitric oxide synthase, inducible. Chain: a, b. Fragment: inducible nitric oxide synthase oxygenase domain (residues 77-495). Synonym: nos, type ii, inducible nos, inos, macrophage nos, mac-nos. Engineered: yes
Source: Mus musculus. House mouse. Organism_taxid: 10090. Gene: nos2, inosl. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Dimer (from PDB file)
Resolution:
2.90Å     R-factor:   0.207     R-free:   0.262
Authors: R.Fedorov,R.Vasan,D.K.Ghosh,I.Schlichting
Key ref:
R.Fedorov et al. (2004). Structures of nitric oxide synthase isoforms complexed with the inhibitor AR-R17477 suggest a rational basis for specificity and inhibitor design. Proc Natl Acad Sci U S A, 101, 5892-5897. PubMed id: 15071192 DOI: 10.1073/pnas.0306588101
Date:
16-Feb-04     Release date:   01-Jun-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P29477  (NOS2_MOUSE) -  Nitric oxide synthase, inducible from Mus musculus
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		1144 a.a.
419 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.1.14.13.39  - nitric-oxide synthase (NADPH).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      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

 

 
    reference    
 
 
DOI no: 10.1073/pnas.0306588101 Proc Natl Acad Sci U S A 101:5892-5897 (2004)
PubMed id: 15071192  
 
 
Structures of nitric oxide synthase isoforms complexed with the inhibitor AR-R17477 suggest a rational basis for specificity and inhibitor design.
R.Fedorov, R.Vasan, D.K.Ghosh, I.Schlichting.
 
  ABSTRACT  
 
The high level of amino acid conservation and structural similarity of the substrate-binding sites of the oxygenase domains of the nitric oxide synthase (NOS) isoforms (eNOSoxy, iNOSoxy, nNOSoxy) make the interpretation of the structural basis of inhibitor isoform specificity a challenge, and provide few clues for the design of new selective compounds. Crystal structures of iNOSoxy and nNOSoxy complexed with the neuronal NOS-specific inhibitor AR-R17447 suggest that specificity is provided by the interaction of the chlorophenyl group with an isoform-unique substrate access channel residue (L337 in rat neuronal NOS, N115 in mouse inducible NOS). This is confirmed by biochemical analysis of site-directed mutants. Inhibitors combining guanidinium-like structural motifs with long chains specifically targeting this residue are good candidates for rational isoform-specific drug design. Based on this finding, modifications of AR-R17447 to improve the specificity for the human isoforms are suggested.
 
  Selected figure(s)  
 
Figure 1.
Fig. 1. F[obs] - F[calc] electron density omit maps contoured at 3 superimposed with the final model of the inhibitor AR-R17477 bound to nNOSoxy and the two crystallographically independent molecules in the asymmetric unit of iNOSoxy crystals (mol.1 and mol.2). 		Figure 2.
Fig. 2. Schematic representation of the interactions of AR-R17477 and nNOSoxy and iNOSoxy (two molecules in asymmetric unit, two conformations each). Dashed lines correspond to hydrogen bonds, dotted lines correspond to van der Waals interactions.
 
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19465397 A.Pavelka, E.Chovancova, and J.Damborsky (2009).
HotSpot Wizard: a web server for identification of hot spots in protein engineering.
  Nucleic Acids Res, 37, W376-W383.  
19537690 J.Fang, H.Ji, G.R.Lawton, F.Xue, L.J.Roman, and R.B.Silverman (2009).
L337H mutant of rat neuronal nitric oxide synthase resembles human neuronal nitric oxide synthase toward inhibitors.
  J Med Chem, 52, 4533-4537.  
19362065 J.Fang, and R.B.Silverman (2009).
A cellular model for screening neuronal nitric oxide synthase inhibitors.
  Anal Biochem, 390, 74-78.  
19701186 M.Pavlova, M.Klvana, Z.Prokop, R.Chaloupkova, P.Banas, M.Otyepka, R.C.Wade, M.Tsuda, Y.Nagata, and J.Damborsky (2009).
Redesigning dehalogenase access tunnels as a strategy for degrading an anthropogenic substrate.
  Nat Chem Biol, 5, 727-733.  
18193303 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.
  J Mol Model, 14, 215-224.  
16543809 W.Li, N.T.Lee, H.Fu, K.K.Kan, Y.Pang, M.Li, K.W.Tsim, X.Li, and Y.Han (2006).
Neuroprotection via inhibition of nitric oxide synthase by bis(7)-tacrine.
  Neuroreport, 17, 471-474.  
15537755 T.L.Arakaki, J.A.Pezza, M.A.Cronin, C.E.Hopkins, D.B.Zimmer, D.R.Tolan, and K.N.Allen (2004).
Structure of human brain fructose 1,6-(bis)phosphate aldolase: linking isozyme structure with function.
  Protein Sci, 13, 3077-3084.
PDB code: 1xfb
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 code is shown on the right.

 

spacer
spacer