1RS8

Bovine endothelial NOS heme domain with D-lysine-D-nitroarginine amide bound

Summary for 1RS8

• Entry DOI: 10.2210/pdb1rs8/pdb
• Related: 1RS6 1RS7 1RS9
• Descriptor: Nitric-oxide synthase, endothelial, CACODYLATE ION, ACETATE ION, ... (9 entities in total)
• Functional Keywords: nitric oxide synthase, oxidoreductase, heme-enzyme
• Biological source: Bos taurus (cattle)
• Cellular location: Cell membrane: P29473
• Total number of polymer chains: 2
• Total formula weight: 96761.99

Authors

Flinspach, M.,Li, H.,Jamal, J.,Yang, W.,Huang, H.,Silverman, R.B.,Poulos, T.L. (deposition date: 2003-12-09, release date: 2004-06-15, Last modification date: 2024-02-14)

Primary citation

Flinspach, M.,Li, H.,Jamal, J.,Yang, W.,Huang, H.,Silverman, R.B.,Poulos, T.L.
Structures of the neuronal and endothelial nitric oxide synthase heme domain with D-nitroarginine-containing dipeptide inhibitors bound.
Biochemistry, 43:5181-5187, 2004

PubMed Abstract: In a continuing effort to unravel the structural basis for isoform-selective inhibition of nitric oxide synthase (NOS) by various inhibitors, we have determined the crystal structures of the nNOS and eNOS heme domain bound with two D-nitroarginine-containing dipeptide inhibitors, D-Lys-D-Arg(NO)2-NH(2) and D-Phe-D-Arg(NO)2-NH(2). These two dipeptide inhibitors exhibit similar binding modes in the two constitutive NOS isozymes, which is consistent with the similar binding affinities for the two isoforms as determined by K(i) measurements. The D-nitroarginine-containing dipeptide inhibitors are not distinguished by the amino acid difference between nNOS and eNOS (Asp 597 and Asn 368, respectively) which is key in controlling isoform selection for nNOS over eNOS observed for the L-nitroarginine-containing dipeptide inhibitors reported previously [Flinspach, M., et al. (2004) Nat. Struct. Mol. Biol. 11, 54-59]. The lack of a free alpha-amino group on the D-nitroarginine moiety makes the dipeptide inhibitor steer away from the amino acid binding pocket near the active site. This allows the inhibitor to extend into the solvent-accessible channel farther away from the active site, which enables the inhibitors to explore new isoform-specific enzyme-inhibitor interactions. This might be the structural basis for why these D-nitroarginine-containing inhibitors are selective for nNOS (or eNOS) over iNOS.

PubMed: 15122883
DOI: 10.1021/bi0361867

Experimental method

X-RAY DIFFRACTION (2.3 Å)