From Proteopedia

proteopedia linkproteopedia link

spinqualitylabelsall models 2oyu, resolution 2.700Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Indomethacin-(S)-alpha-ethyl-ethanolamide bound to Cyclooxygenase-1

Overview

The modification of the nonselective nonsteroidal anti-inflammatory drug, indomethacin, by amidation presents a promising strategy for designing, novel cyclooxygenase (COX)-2-selective inhibitors. A series of, alpha-substituted indomethacin ethanolamides, which exist as, R/S-enantiomeric pairs, provides a means to study the impact of, stereochemistry on COX inhibition. Comparative studies revealed that the, R- and S-enantiomers of the alpha-substituted analogs inhibit COX-2 with, almost equal efficacy, whereas COX-1 is selectively inhibited by the, S-enantiomers. Mutagenesis studies have not been able to identify residues, that manifest the enantioselectivity in COX-1. In an effort to understand, the structural impact of chirality on COX-1 selectivity, the crystal, structures of ovine COX-1 in complexes with an enantiomeric pair of these, indomethacin ethanolamides were determined at resolutions between 2.75 and, 2.85 A. These structures reveal unique, enantiomer-selective interactions, within the COX-1 side pocket region that stabilize drug binding and, account for the chiral selectivity observed with the (S)-alpha-substituted, indomethacin ethanolamides. Kinetic analysis of binding demonstrates that, both inhibitors bind quickly utilizing a two-step mechanism. However, the, second binding step is readily reversible for the R-enantiomer, whereas, for the S-enantiomer, it is not. These studies establish for the first, time the structural and kinetic basis of high affinity binding of a, neutral inhibitor to COX-1 and demonstrate that the side pocket of COX-1, previously thought to be sterically inaccessible, can serve as a binding, pocket for inhibitor association.

About this Structure

2OYU is a Single protein structure of sequence from Ovis aries with , and as ligands. Active as Prostaglandin-endoperoxide synthase, with EC number 1.14.99.1 Full crystallographic information is available from OCA.

Reference

Structural basis of enantioselective inhibition of cyclooxygenase-1 by S-alpha-substituted indomethacin ethanolamides., Harman CA, Turman MV, Kozak KR, Marnett LJ, Smith WL, Garavito RM, J Biol Chem. 2007 Sep 21;282(38):28096-105. Epub 2007 Jul 26. PMID:17656360

Page seeded by OCA on Wed Jan 23 12:56:36 2008