1p6l

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spinqualitylabelsall models 1p6l, resolution 2.35Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Bovine endothelial NOS heme domain with L-N(omega)-nitroarginine-2,4-L-diaminobutyric amide bound

Overview

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 Structure

1P6L 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.

Reference

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

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