1P6J

Rat neuronal NOS heme domain with L-N(omega)-nitroarginine-(4R)-amino-L-proline amide bound

Summary for 1P6J

• Entry DOI: 10.2210/pdb1p6j/pdb
• Descriptor: Nitric-oxide synthase, brain, ACETATE ION, ZINC ION, ... (7 entities in total)
• Functional Keywords: nitric oxide synthase, oxidoreductase, heme-enzyme
• Biological source: Rattus norvegicus (Norway rat)
• Cellular location: Cell membrane, sarcolemma ; Peripheral membrane protein : P29476
• Total number of polymer chains: 2
• Total formula weight: 100070.61

Authors

Flinspach, M.L.,Li, H.,Jamal, J.,Yang, W.,Huang, H.,Hah, J.-M.,Gomez-Vidal, J.A.,Litzinger, E.A.,Silverman, R.B.,Poulos, T.L. (deposition date: 2003-04-29, release date: 2004-01-13, Last modification date: 2024-02-14)

Primary citation

Flinspach, M.L.,Li, H.,Jamal, J.,Yang, W.,Huang, H.,Hah, J.M.,Gomez-Vidal, J.A.,Litzinger, E.A.,Silverman, R.B.,Poulos, T.L.
Structural basis for dipeptide amide isoform-selective inhibition of neuronal nitric oxide synthase.
Nat.Struct.Mol.Biol., 11:54-59, 2004

PubMed 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.

PubMed: 14718923
DOI: 10.1038/nsmb704

Experimental method

X-RAY DIFFRACTION (2 Å)