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| | ==Crystal structure of fatty acid amide hydrolase== | | ==Crystal structure of fatty acid amide hydrolase== |
| - | <StructureSection load='3qj8' size='340' side='right' caption='[[3qj8]], [[Resolution|resolution]] 2.90Å' scene=''> | + | <StructureSection load='3qj8' size='340' side='right'caption='[[3qj8]], [[Resolution|resolution]] 2.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3qj8]] 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=3QJ8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3QJ8 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3qj8]] 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=3QJ8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3QJ8 FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3qj9|3qj9]], [[3qk5|3qk5]], [[3qkv|3qkv]]</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]] 2.9Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Faah, 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=3qj8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qj8 OCA], [https://pdbe.org/3qj8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3qj8 RCSB], [https://www.ebi.ac.uk/pdbsum/3qj8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3qj8 ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Fatty_acid_amide_hydrolase Fatty acid amide hydrolase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.1.99 3.5.1.99] </span></td></tr>
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| - | <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=3qj8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qj8 OCA], [http://pdbe.org/3qj8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3qj8 RCSB], [http://www.ebi.ac.uk/pdbsum/3qj8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3qj8 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). |
| - | <div style="background-color:#fffaf0;">
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| - | == Publication Abstract from PubMed ==
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| - | Fatty acid amide hydrolase (FAAH), an amidase-signature family member, is an integral membrane enzyme that degrades lipid amides including the endogenous cannabinoid anandamide and the sleep-inducing molecule oleamide. Both genetic knock out and pharmacological administration of FAAH inhibitors in rodent models result in analgesic, anxiolytic, and antiinflammatory phenotypes. Targeting FAAH activity, therefore, presents a promising new therapeutic strategy for the treatment of pain and other neurological-related or inflammatory disorders. Nearly all FAAH inhibitors known to date attain their binding potency through a reversible or irreversible covalent modification of the nucleophile Ser241 in the unusual Ser-Ser-Lys catalytic triad. Here, we report the discovery and mechanism of action of a series of ketobenzimidazoles as unique and potent noncovalent FAAH inhibitors. Compound 2, a representative of these ketobenzimidazoles, was designed from a series of ureas that were identified from high-throughput screening. While urea compound 1 is characterized as an irreversible covalent inhibitor, the cocrystal structure of FAAH complexed with compound 2 reveals that these ketobenzimidazoles, though containing a carbonyl moiety, do not covalently modify Ser241. These inhibitors achieve potent inhibition of FAAH activity primarily from shape complementarity to the active site and through numerous hydrophobic interactions. These noncovalent compounds exhibit excellent selectivity and good pharmacokinetic properties. The discovery of this distinctive class of inhibitors opens a new avenue for modulating FAAH activity through nonmechanism-based inhibition.
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| - | Discovery and molecular basis of potent noncovalent inhibitors of fatty acid amide hydrolase (FAAH).,Min X, Thibault ST, Porter AC, Gustin DJ, Carlson TJ, Xu H, Lindstrom M, Xu G, Uyeda C, Ma Z, Li Y, Kayser F, Walker NP, Wang Z Proc Natl Acad Sci U S A. 2011 May 3;108(18):7379-84. Epub 2011 Apr 18. PMID:21502526<ref>PMID:21502526</ref>
| + | ==See Also== |
| - | | + | *[[Fatty acid amide hydrolase|Fatty acid amide hydrolase]] |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
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| - | <div class="pdbe-citations 3qj8" style="background-color:#fffaf0;"></div>
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| - | == References ==
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| - | <references/>
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Buffalo rat]] | + | [[Category: Large Structures]] |
| - | [[Category: Fatty acid amide hydrolase]] | + | [[Category: Rattus norvegicus]] |
| - | [[Category: Min, X]] | + | [[Category: Min X]] |
| - | [[Category: Walker, N P.C]] | + | [[Category: Walker NPC]] |
| - | [[Category: Wang, Z]] | + | [[Category: Wang Z]] |
| - | [[Category: Apo structure]]
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| - | [[Category: Faah]]
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| - | [[Category: Fatty-acid amide hydrolase]]
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| - | [[Category: Hydrolase]]
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