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2oye

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2oye, resolution 2.85Å ()
Ligands: , , , , , ,
Activity: Prostaglandin-endoperoxide synthase, with EC number 1.14.99.1
Related: 1pgg, 1pgf, 1cqe, 1eqe
Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

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

Publication Abstract from PubMed

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.

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

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

About this Structure

2oye is a 1 chain structure with sequence from Ovis aries. Full crystallographic information is available from OCA.

See Also

Reference

  • Harman CA, Turman MV, Kozak KR, Marnett LJ, Smith WL, Garavito RM. Structural basis of enantioselective inhibition of cyclooxygenase-1 by S-alpha-substituted indomethacin ethanolamides. J Biol Chem. 2007 Sep 21;282(38):28096-105. Epub 2007 Jul 26. PMID:17656360 doi:10.1074/jbc.M701335200

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