2OYU

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

Summary for 2OYU

• Entry DOI: 10.2210/pdb2oyu/pdb
• Related: 1CQE 1EQE 1PGF 1PGG 2OYE
• Descriptor: Prostaglandin G/H synthase 1, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• Functional Keywords: cox, pghs, indomethacin, nsaid, heme, oxidoreductase
• Biological source: Ovis aries (sheep)
• Total number of polymer chains: 1
• Total formula weight: 71916.59

Authors

Harman, C.A.,Garavito, R.M. (deposition date: 2007-02-23, release date: 2007-07-24, Last modification date: 2023-08-30)

Primary citation

Harman, C.A.,Turman, M.V.,Kozak, K.R.,Marnett, L.J.,Smith, W.L.,Garavito, R.M.
Structural basis of enantioselective inhibition of cyclooxygenase-1 by S-alpha-substituted indomethacin ethanolamides.
J.Biol.Chem., 282:28096-28105, 2007

PubMed Abstract: 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.

PubMed: 17656360
DOI: 10.1074/jbc.M701335200

Experimental method

X-RAY DIFFRACTION (2.7 Å)