1ZZU

Rat nNOS D597N/M336V double mutant with L-N(omega)-Nitroarginine-2,4-L-Diaminobutyric Amide Bound

Summary for 1ZZU

• Entry DOI: 10.2210/pdb1zzu/pdb
• Related: 1P6H
• Descriptor: Nitric-oxide synthase, brain, ACETATE ION, ZINC ION, ... (9 entities in total)
• Functional Keywords: oxydoreductase, enzyme-inhibtor complex, oxidoreductase
• Biological source: Rattus norvegicus (Norway rat)
• Cellular location: Cell membrane, sarcolemma ; Peripheral membrane protein : P29476
• Total number of polymer chains: 2
• Total formula weight: 100242.60

Authors

Li, H.,Flinspach, M.L.,Igarashi, J.,Jamal, J.,Yang, W.,Gomez-Vidal, J.A.,Litzinger, E.A.,Silverman, R.B.,Poulos, T.L. (deposition date: 2005-06-14, release date: 2005-12-06, Last modification date: 2024-02-14)

Primary citation

Li, H.,Flinspach, M.L.,Igarashi, J.,Jamal, J.,Yang, W.,Litzinger, E.A.,Huang, H.,Erdal, E.P.,Silverman, R.B.,Poulos, T.L.
Exploring the Binding Conformations of Bulkier Dipeptide Amide Inhibitors in Constitutive Nitric Oxide Synthases.
Biochemistry, 44:15222-15229, 2005

PubMed Abstract: A series of L-nitroarginine-based dipeptide inhibitors are highly selective for neuronal nitric oxide synthase (nNOS) over the endothelial isoform (eNOS). Crystal structures of these dipeptides bound to both isoforms revealed two different conformations, curled in nNOS and extended in eNOS, corresponding to higher and lower binding affinity to the two isoforms, respectively. In previous studies we found that the primary reason for selectivity is that Asp597 in nNOS, which is Asn368 in eNOS, provides greater electrostatic stabilization in the inhibitor complex. While this is the case for smaller dipeptide inhibitors, electrostatic stabilization may no longer be the sole determinant for isoform selectivity with bulkier dipeptide inhibitors. Another residue farther away from the active site, Met336 in nNOS (Val106 in eNOS), is in contact with bulkier dipeptide inhibitors. Double mutants were made to exchange the D597/M336 pair in nNOS with N368/V106 in eNOS. Here we report crystal structures and inhibition constants for bulkier dipeptide inhibitors bound to nNOS and eNOS that illustrate the important role played by residues near the entry to the active site in isoform selective inhibition.

PubMed: 16285725
DOI: 10.1021/bi0513610

Experimental method

X-RAY DIFFRACTION (1.9 Å)