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| - | [[Image:2oyu.gif|left|200px]] | + | {{Seed}} |
| | + | [[Image:2oyu.png|left|200px]] |
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| | {{STRUCTURE_2oyu| PDB=2oyu | SCENE= }} | | {{STRUCTURE_2oyu| PDB=2oyu | SCENE= }} |
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| - | '''Indomethacin-(S)-alpha-ethyl-ethanolamide bound to Cyclooxygenase-1'''
| + | ===Indomethacin-(S)-alpha-ethyl-ethanolamide bound to Cyclooxygenase-1=== |
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| - | ==Overview==
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| - | 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. | + | The line below this paragraph, {{ABSTRACT_PUBMED_17656360}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 17656360 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_17656360}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Oxidoreductase]] | | [[Category: Oxidoreductase]] |
| | [[Category: Pgh]] | | [[Category: Pgh]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 11:57:27 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 22:14:13 2008'' |
Revision as of 19:14, 28 July 2008
Template:STRUCTURE 2oyu
Indomethacin-(S)-alpha-ethyl-ethanolamide bound to Cyclooxygenase-1
Template:ABSTRACT PUBMED 17656360
About this Structure
2OYU is a Single protein structure of sequence from Ovis aries. 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 Mon Jul 28 22:14:13 2008
