|
|
| (One intermediate revision not shown.) |
| Line 1: |
Line 1: |
| | | | |
| | ==Crystal Structure Analysis of a Oleyl/Oxadiazole/pyridine Inhibitor Bound to a Humanized Variant of Fatty Acid Amide Hydrolase== | | ==Crystal Structure Analysis of a Oleyl/Oxadiazole/pyridine Inhibitor Bound to a Humanized Variant of Fatty Acid Amide Hydrolase== |
| - | <StructureSection load='3k84' size='340' side='right' caption='[[3k84]], [[Resolution|resolution]] 2.25Å' scene=''> | + | <StructureSection load='3k84' size='340' side='right'caption='[[3k84]], [[Resolution|resolution]] 2.25Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3k84]] 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=3K84 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3K84 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3k84]] 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=3K84 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3K84 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=K84:(9Z)-1-(5-PYRIDIN-2-YL-1,3,4-OXADIAZOL-2-YL)OCTADEC-9-EN-1-ONE'>K84</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.25Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2wj1|2wj1]], [[2wj2|2wj2]], [[3k7f|3k7f]], [[3k83|3k83]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=K84:(9Z)-1-(5-PYRIDIN-2-YL-1,3,4-OXADIAZOL-2-YL)OCTADEC-9-EN-1-ONE'>K84</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Faah, faah-1, Faah1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat])</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=3k84 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3k84 OCA], [https://pdbe.org/3k84 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3k84 RCSB], [https://www.ebi.ac.uk/pdbsum/3k84 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3k84 ProSAT]</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=3k84 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3k84 OCA], [http://pdbe.org/3k84 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3k84 RCSB], [http://www.ebi.ac.uk/pdbsum/3k84 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3k84 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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). | + | [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 == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| Line 37: |
Line 36: |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Buffalo rat]] | + | [[Category: Large Structures]] |
| - | [[Category: Boger, D L]] | + | [[Category: Rattus norvegicus]] |
| - | [[Category: Mileni, M]] | + | [[Category: Boger DL]] |
| - | [[Category: Stevens, R C]] | + | [[Category: Mileni M]] |
| - | [[Category: Alpha-ketoheterocycle]] | + | [[Category: Stevens RC]] |
| - | [[Category: Conjugate]]
| + | |
| - | [[Category: Covalent modification]]
| + | |
| - | [[Category: Endocannabinoid]]
| + | |
| - | [[Category: Faah]]
| + | |
| - | [[Category: Fatty acid]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Membrane]]
| + | |
| - | [[Category: Monotopic]]
| + | |
| - | [[Category: Oxadiazole]]
| + | |
| - | [[Category: Oxazole]]
| + | |
| - | [[Category: Reversible inhibitor]]
| + | |
| - | [[Category: Serine hydrolase]]
| + | |
| - | [[Category: Transmembrane]]
| + | |
| Structural highlights
Function
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
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Mileni M, Garfunkle J, Ezzili C, Kimball FS, Cravatt BF, Stevens RC, Boger DL. X-ray Crystallographic Analysis of alpha-Ketoheterocycle Inhibitors Bound to a Humanized Variant of Fatty Acid Amide Hydrolase. J Med Chem. 2009 Nov 19. PMID:19924997 doi:10.1021/jm9012196
|
