1q2o
|
Bovine endothelial nitric oxide synthase N368D mutant heme domain dimer with L-N(omega)-nitroarginine-2,4-L-diaminobutyramide bound
OverviewOverview
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.
About this StructureAbout this Structure
1Q2O is a Single protein structure of sequence from Bos taurus with CAC, ACT, ZN, HEM, H4B, DP1 and GOL as ligands. Active as Nitric-oxide synthase, with EC number 1.14.13.39 Full crystallographic information is available from OCA.
ReferenceReference
Structural basis for dipeptide amide isoform-selective inhibition of neuronal nitric oxide synthase., Flinspach ML, Li H, Jamal J, Yang W, Huang H, Hah JM, Gomez-Vidal JA, Litzinger EA, Silverman RB, Poulos TL, Nat Struct Mol Biol. 2004 Jan;11(1):54-9. Epub 2003 Dec 29. PMID:14718923
Page seeded by OCA on Wed Nov 21 00:20:12 2007