3k83: Difference between revisions
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< | ==Crystal Structure Analysis of a Biphenyl/Oxazole/Carboxypyridine alpha-ketoheterocycle Inhibitor Bound to a Humanized Variant of Fatty Acid Amide Hydrolase== | ||
<StructureSection load='3k83' size='340' side='right'caption='[[3k83]], [[Resolution|resolution]] 2.25Å' scene=''> | |||
You may | == Structural highlights == | ||
or the | <table><tr><td colspan='2'>[[3k83]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3K83 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3K83 FirstGlance]. <br> | ||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.251Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1DO:1-DODECANOL'>1DO</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=F27:6-[2-(3-BIPHENYL-4-YLPROPANOYL)-1,3-OXAZOL-5-YL]PYRIDINE-2-CARBOXYLIC+ACID'>F27</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3k83 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3k83 OCA], [https://pdbe.org/3k83 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3k83 RCSB], [https://www.ebi.ac.uk/pdbsum/3k83 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3k83 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/FAAH1_RAT FAAH1_RAT] Degrades bioactive fatty acid amides like oleamide, the endogenous cannabinoid, anandamide and myristic amide to their corresponding acids, thereby serving to terminate the signaling functions of these molecules. Hydrolyzes polyunsaturated substrate anandamide preferentially as compared to monounsaturated substrates (By similarity). | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/k8/3k83_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</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/main_output.php?pdb_ID=3k83 ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Three cocrystal X-ray structures of the alpha-ketoheterocycle inhibitors 3-5 bound to a humanized variant of fatty acid amide hydrolase (FAAH) are disclosed and comparatively discussed alongside those of 1 (OL-135) and its isomer 2. These five X-ray structures systematically probe each of the three active site regions key to substrate or inhibitor binding: (1) the conformationally mobile acyl chain-binding pocket and membrane access channel responsible for fatty acid amide substrate and inhibitor acyl chain binding, (2) the atypical active site catalytic residues and surrounding oxyanion hole that covalently binds the core of the alpha-ketoheterocycle inhibitors captured as deprotonated hemiketals mimicking the tetrahedral intermediate of the enzyme-catalyzed reaction, and (3) the cytosolic port and its uniquely important imbedded ordered water molecules and a newly identified anion binding site. The detailed analysis of their key active site interactions and their implications on the interpretation of the available structure-activity relationships are discussed providing important insights for future design. | |||
X-ray Crystallographic Analysis of alpha-Ketoheterocycle Inhibitors Bound to a Humanized Variant of Fatty Acid Amide Hydrolase.,Mileni M, Garfunkle J, Ezzili C, Kimball FS, Cravatt BF, Stevens RC, Boger DL J Med Chem. 2009 Nov 19. PMID:19924997<ref>PMID:19924997</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3k83" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Fatty acid amide hydrolase|Fatty acid amide hydrolase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
== | [[Category: Large Structures]] | ||
== | |||
< | |||
[[Category: Rattus norvegicus]] | [[Category: Rattus norvegicus]] | ||
[[Category: Boger | [[Category: Boger DL]] | ||
[[Category: Mileni | [[Category: Mileni M]] | ||
[[Category: Stevens | [[Category: Stevens RC]] | ||
Latest revision as of 13:04, 6 November 2024
Crystal Structure Analysis of a Biphenyl/Oxazole/Carboxypyridine alpha-ketoheterocycle Inhibitor Bound to a Humanized Variant of Fatty Acid Amide HydrolaseCrystal Structure Analysis of a Biphenyl/Oxazole/Carboxypyridine alpha-ketoheterocycle Inhibitor Bound to a Humanized Variant of Fatty Acid Amide Hydrolase
Structural highlights
FunctionFAAH1_RAT Degrades bioactive fatty acid amides like oleamide, the endogenous cannabinoid, anandamide and myristic amide to their corresponding acids, thereby serving to terminate the signaling functions of these molecules. Hydrolyzes polyunsaturated substrate anandamide preferentially as compared to monounsaturated substrates (By similarity). 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 PubMedThree cocrystal X-ray structures of the alpha-ketoheterocycle inhibitors 3-5 bound to a humanized variant of fatty acid amide hydrolase (FAAH) are disclosed and comparatively discussed alongside those of 1 (OL-135) and its isomer 2. These five X-ray structures systematically probe each of the three active site regions key to substrate or inhibitor binding: (1) the conformationally mobile acyl chain-binding pocket and membrane access channel responsible for fatty acid amide substrate and inhibitor acyl chain binding, (2) the atypical active site catalytic residues and surrounding oxyanion hole that covalently binds the core of the alpha-ketoheterocycle inhibitors captured as deprotonated hemiketals mimicking the tetrahedral intermediate of the enzyme-catalyzed reaction, and (3) the cytosolic port and its uniquely important imbedded ordered water molecules and a newly identified anion binding site. The detailed analysis of their key active site interactions and their implications on the interpretation of the available structure-activity relationships are discussed providing important insights for future design. X-ray Crystallographic Analysis of alpha-Ketoheterocycle Inhibitors Bound to a Humanized Variant of Fatty Acid Amide Hydrolase.,Mileni M, Garfunkle J, Ezzili C, Kimball FS, Cravatt BF, Stevens RC, Boger DL J Med Chem. 2009 Nov 19. PMID:19924997[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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