1zzt

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Revision as of 05:38, 21 November 2007

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spinqualitylabelsall models 1zzt, resolution 2.14Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Bovine eNOS N368D/V106M double mutant with L-N(omega)-Nitroarginine-(4R)-Amino-L-Proline Amide Bound

Overview

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.

About this Structure

1ZZT is a Single protein structure of sequence from Bos taurus with ACT, ZN, HEM, H4B and DP9 as ligands. Active as Nitric-oxide synthase, with EC number 1.14.13.39 Full crystallographic information is available from OCA.

Reference

Exploring the binding conformations of bulkier dipeptide amide inhibitors in constitutive nitric oxide synthases., Li H, Flinspach ML, Igarashi J, Jamal J, Yang W, Gomez-Vidal JA, Litzinger EA, Huang H, Erdal EP, Silverman RB, Poulos TL, Biochemistry. 2005 Nov 22;44(46):15222-9. PMID:16285725

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