2oye: Difference between revisions
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'''Indomethacin-(R)-alpha-ethyl-ethanolamide bound to Cyclooxygenase-1''' | {{Structure | ||
|PDB= 2oye |SIZE=350|CAPTION= <scene name='initialview01'>2oye</scene>, resolution 2.850Å | |||
|SITE= | |||
|LIGAND= <scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=FLC:CITRATE+ANION'>FLC</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene> and <scene name='pdbligand=IM8:2-[1-(4-CHLOROBENZOYL)-5-METHOXY-2-METHYL-1H-INDOL-3-YL]-N-[(1R)-1-(HYDROXYMETHYL)PROPYL]ACETAMIDE'>IM8</scene> | |||
|ACTIVITY= [http://en.wikipedia.org/wiki/Prostaglandin-endoperoxide_synthase Prostaglandin-endoperoxide synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.99.1 1.14.99.1] | |||
|GENE= | |||
}} | |||
'''Indomethacin-(R)-alpha-ethyl-ethanolamide bound to Cyclooxygenase-1''' | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
2OYE is a [ | 2OYE is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Ovis_aries Ovis aries]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2OYE OCA]. | ||
==Reference== | ==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:[http:// | 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:[http://www.ncbi.nlm.nih.gov/pubmed/17656360 17656360] | ||
[[Category: Ovis aries]] | [[Category: Ovis aries]] | ||
[[Category: Prostaglandin-endoperoxide synthase]] | [[Category: Prostaglandin-endoperoxide synthase]] | ||
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[[Category: nsaid]] | [[Category: nsaid]] | ||
[[Category: oxidoreductase]] | [[Category: oxidoreductase]] | ||
[[Category: | [[Category: pgh]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 18:06:14 2008'' | ||
Revision as of 19:06, 20 March 2008
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| , resolution 2.850Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , , and | ||||||
| Activity: | Prostaglandin-endoperoxide synthase, with EC number 1.14.99.1 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Indomethacin-(R)-alpha-ethyl-ethanolamide bound to Cyclooxygenase-1
OverviewOverview
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 StructureAbout this Structure
2OYE is a Single protein structure of sequence from Ovis aries. Full crystallographic information is available from OCA.
ReferenceReference
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
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