Description
Experimental Technique/Method:X-RAY DIFFRACTION
Resolution:1.9
Classification:OXIDOREDUCTASE
Release Date:2004-01-13
Deposition Date:2003-04-29
Revision Date:2008-04-29#2011-07-13
Molecular Weight:99904.52
Macromolecule Type:Protein
Residue Count:842
Atom Site Count:6817
DOI:10.2210/pdb1p6i/pdb
Abstract:
Three nitric oxide synthase (NOS) isoforms, eNOS, nNOS and iNOS, generate nitric oxide (NO) crucial to the cardiovascular, nervous and host defense systems, respectively. Development of isoform-selective NOS inhibitors is of considerable therapeutic importance. Crystal structures of nNOS-selective dipeptide inhibitors in complex with both nNOS and eNOS were solved and the inhibitors were found to adopt a curled conformation in nNOS but an extended conformation in eNOS. We hypothesized that a single-residue difference in the active site, Asp597 (nNOS) versus Asn368 (eNOS), is responsible for the favored binding in nNOS. In the D597N nNOS mutant crystal structure, a bound inhibitor switches to the extended conformation and its inhibition of nNOS decreases >200-fold. Therefore, a single-residue difference is responsible for more than two orders of magnitude selectivity in inhibition of nNOS over eNOS by L-N(omega)-nitroarginine-containing dipeptide inhibitors.
Resolution:1.9
Classification:OXIDOREDUCTASE
Release Date:2004-01-13
Deposition Date:2003-04-29
Revision Date:2008-04-29#2011-07-13
Molecular Weight:99904.52
Macromolecule Type:Protein
Residue Count:842
Atom Site Count:6817
DOI:10.2210/pdb1p6i/pdb
Abstract:
Three nitric oxide synthase (NOS) isoforms, eNOS, nNOS and iNOS, generate nitric oxide (NO) crucial to the cardiovascular, nervous and host defense systems, respectively. Development of isoform-selective NOS inhibitors is of considerable therapeutic importance. Crystal structures of nNOS-selective dipeptide inhibitors in complex with both nNOS and eNOS were solved and the inhibitors were found to adopt a curled conformation in nNOS but an extended conformation in eNOS. We hypothesized that a single-residue difference in the active site, Asp597 (nNOS) versus Asn368 (eNOS), is responsible for the favored binding in nNOS. In the D597N nNOS mutant crystal structure, a bound inhibitor switches to the extended conformation and its inhibition of nNOS decreases >200-fold. Therefore, a single-residue difference is responsible for more than two orders of magnitude selectivity in inhibition of nNOS over eNOS by L-N(omega)-nitroarginine-containing dipeptide inhibitors.
| Date made available | 2004 |
|---|---|
| Publisher | RCSB-PDB |