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2oyu

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(New page: 200px<br /><applet load="2oyu" size="450" color="white" frame="true" align="right" spinBox="true" caption="2oyu, resolution 2.700&Aring;" /> '''Indomethacin-(S)-al...)
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[[Image:2oyu.gif|left|200px]]<br /><applet load="2oyu" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="2oyu, resolution 2.700&Aring;" />
 
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'''Indomethacin-(S)-alpha-ethyl-ethanolamide bound to Cyclooxygenase-1'''<br />
 
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==Overview==
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==Indomethacin-(S)-alpha-ethyl-ethanolamide bound to Cyclooxygenase-1==
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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.
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<StructureSection load='2oyu' size='340' side='right'caption='[[2oyu]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2oyu]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Ovis_aries Ovis aries]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2OYU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2OYU FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=IMS:2-[1-(4-CHLOROBENZOYL)-5-METHOXY-2-METHYL-1H-INDOL-3-YL]-N-[(1S)-1-(HYDROXYMETHYL)PROPYL]ACETAMIDE'>IMS</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2oyu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2oyu OCA], [https://pdbe.org/2oyu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2oyu RCSB], [https://www.ebi.ac.uk/pdbsum/2oyu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2oyu ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/PGH1_SHEEP PGH1_SHEEP] May play an important role in regulating or promoting cell proliferation in some normal and neoplastically transformed cells.
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/oy/2oyu_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2oyu ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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==About this Structure==
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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<ref>PMID:17656360</ref>
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2OYU is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Ovis_aries Ovis aries] with BOG, IMS and HEM as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2OYU OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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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://ispc.weizmann.ac.il//pmbin/getpm?pmid=17656360 17656360]
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</div>
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[[Category: Ovis aries]]
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<div class="pdbe-citations 2oyu" style="background-color:#fffaf0;"></div>
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[[Category: Prostaglandin-endoperoxide synthase]]
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[[Category: Single protein]]
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[[Category: Garavito, R.M.]]
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[[Category: Harman, C.A.]]
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[[Category: BOG]]
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[[Category: HEM]]
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[[Category: IMS]]
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[[Category: cox]]
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[[Category: heme]]
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[[Category: indomethacin]]
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[[Category: nsaid]]
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[[Category: oxidoreductase]]
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[[Category: pghs]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 13:22:08 2007''
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==See Also==
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*[[Cyclooxygenase 3D structures|Cyclooxygenase 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Large Structures]]
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[[Category: Ovis aries]]
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[[Category: Garavito RM]]
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[[Category: Harman CA]]

Current revision

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

PDB ID 2oyu

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