1P6I: Rat Neuronal Nos Heme Domain With (4s)-N-(4-Amino-5- [aminoethyl]aminopentyl)-N'-Nitroguanidine Bound

Citation:
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.
PDB ID: 1P6IDownload
MMDB ID: 26062
PDB Deposition Date: 2003/4/29
Updated in MMDB: 2007/10
Experimental Method:
x-ray diffraction
Resolution: 1.9  Å
Source Organism:
Similar Structures:
Biological Unit for 1P6I: dimeric; determined by author and by software (PISA)
Molecular Components in 1P6I
Label Count Molecule
Proteins (2 molecules)
2
Nitric-oxide Synthase, Brain(Gene symbol: Nos1)
Molecule annotation
Chemicals (9 molecules)
1
2
2
1
3
2
4
2
5
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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