2wj2: Difference between revisions
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<StructureSection load='2wj2' size='340' side='right' caption='[[2wj2]], [[Resolution|resolution]] 2.55Å' scene=''> | <StructureSection load='2wj2' size='340' side='right' caption='[[2wj2]], [[Resolution|resolution]] 2.55Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[2wj2]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/ | <table><tr><td colspan='2'>[[2wj2]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2WJ2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2WJ2 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=OL1:7-PHENYL-1-(5-PYRIDIN-2-YL-1,3-OXAZOL-2-YL)HEPTANE-1,1-DIOL'>OL1</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=OL1:7-PHENYL-1-(5-PYRIDIN-2-YL-1,3-OXAZOL-2-YL)HEPTANE-1,1-DIOL'>OL1</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1mt5|1mt5]], [[2vya|2vya]], [[2wap|2wap]], [[2wj1|2wj1]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1mt5|1mt5]], [[2vya|2vya]], [[2wap|2wap]], [[2wj1|2wj1]]</td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Amidase Amidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.1.4 3.5.1.4] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Amidase Amidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.1.4 3.5.1.4] </span></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2wj2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wj2 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2wj2 RCSB], [http://www.ebi.ac.uk/pdbsum/2wj2 PDBsum]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2wj2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wj2 OCA], [http://pdbe.org/2wj2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2wj2 RCSB], [http://www.ebi.ac.uk/pdbsum/2wj2 PDBsum]</span></td></tr> | ||
</table> | </table> | ||
== Evolutionary Conservation == | == Evolutionary Conservation == | ||
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<text>to colour the structure by Evolutionary Conservation</text> | <text>to colour the structure by Evolutionary Conservation</text> | ||
</jmolCheckbox> | </jmolCheckbox> | ||
</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/ | </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=2wj2 ConSurf]. | ||
<div style="clear:both"></div> | <div style="clear:both"></div> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 2wj2" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
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</StructureSection> | </StructureSection> | ||
[[Category: Amidase]] | [[Category: Amidase]] | ||
[[Category: | [[Category: Buffalo rat]] | ||
[[Category: Boger, D L]] | [[Category: Boger, D L]] | ||
[[Category: Cravatt, B F]] | [[Category: Cravatt, B F]] | ||
Revision as of 06:55, 9 February 2016
3D-CRYSTAL STRUCTURE OF HUMANIZED-RAT FATTY ACID AMIDE HYDROLASE (FAAH) CONJUGATED WITH 7-PHENYL-1-(5-(PYRIDIN-2-YL)OXAZOL-2-YL)HEPTAN-1-ONE, AN ALPHA-KETOOXAZOLE3D-CRYSTAL STRUCTURE OF HUMANIZED-RAT FATTY ACID AMIDE HYDROLASE (FAAH) CONJUGATED WITH 7-PHENYL-1-(5-(PYRIDIN-2-YL)OXAZOL-2-YL)HEPTAN-1-ONE, AN ALPHA-KETOOXAZOLE
Structural highlights
Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe cocrystal X-ray structures of two isomeric alpha-ketooxazole inhibitors (1 (OL-135) and 2) bound to fatty acid amide hydrolase (FAAH), a key enzymatic regulator of endocannabinoid signaling, are disclosed. The active site catalytic Ser241 is covalently bound to the inhibitors' electrophilic carbonyl groups, providing the first structures of FAAH bound to an inhibitor as a deprotonated hemiketal mimicking the enzymatic tetrahedral intermediate. The work also offers a detailed view of the oxyanion hole and an exceptional "in-action" depiction of the unusual Ser-Ser-Lys catalytic triad. These structures capture the first picture of inhibitors that span the active site into the cytosolic port providing new insights that help to explain FAAH's interaction with substrate leaving groups and their role in modulating inhibitor potency and selectivity. The role for the activating central heterocycle is clearly defined and distinguished from that observed in prior applications with serine proteases, reconciling the large electronic effect of attached substituents found unique to this class of inhibitors with FAAH. Additional striking active site flexibility is seen upon binding of the inhibitors, providing insights into the existence of a now well-defined membrane access channel with the disappearance of a spatially independent portion of the acyl chain-binding pocket. Finally, comparison of the structures of OL-135 (1) and its isomer 2 indicates that they bind identically to FAAH, albeit with reversed orientations of the central activating heterocycle, revealing that the terminal 2-pyridyl substituent and the acyl chain phenyl group provide key anchoring interactions and confirming the distinguishing role of the activating oxazole. Binding and inactivation mechanism of a humanized fatty acid amide hydrolase by alpha-ketoheterocycle inhibitors revealed from cocrystal structures.,Mileni M, Garfunkle J, DeMartino JK, Cravatt BF, Boger DL, Stevens RC J Am Chem Soc. 2009 Aug 5;131(30):10497-506. PMID:19722626[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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