1VAF: Inducible Nitric Oxide Synthase Oxygenase Domain Complexed With The Inhibitor Ar-r17477

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.
PDB ID: 1VAFDownload
MMDB ID: 28073
PDB Deposition Date: 2004/2/16
Updated in MMDB: 2017/10
Experimental Method:
x-ray diffraction
Resolution: 2.9  Å
Source Organism:
Similar Structures:
Biological Unit for 1VAF: dimeric; determined by author and by software (PISA,PQS)
Molecular Components in 1VAF
Label Count Molecule
Proteins (2 molecules)
Nitric Oxide Synthase, Inducible(Gene symbol: Nos2)
Molecule annotation
Chemicals (7 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB