3qkv: Difference between revisions
No edit summary |
No edit summary |
||
| (5 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
== | ==Crystal structure of fatty acid amide hydrolase with small molecule compound== | ||
[[http://www.uniprot.org/uniprot/FAAH1_RAT FAAH1_RAT | <StructureSection load='3qkv' size='340' side='right'caption='[[3qkv]], [[Resolution|resolution]] 3.10Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3qkv]] 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=3QKV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3QKV 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]] 3.1Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=QKV:(6-BROMO-1H,4H-SPIRO[1,3-BENZODIOXINE-2,4-PIPERIDIN]-1-YL)METHANOL'>QKV</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=3qkv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qkv OCA], [https://pdbe.org/3qkv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3qkv RCSB], [https://www.ebi.ac.uk/pdbsum/3qkv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3qkv 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). | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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. | |||
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> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
< | </div> | ||
[[Category: | <div class="pdbe-citations 3qkv" 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: Min | [[Category: Min X]] | ||
[[Category: Walker | [[Category: Walker NPC]] | ||
[[Category: Wang | [[Category: Wang Z]] | ||
Latest revision as of 12:36, 30 October 2024
Crystal structure of fatty acid amide hydrolase with small molecule compoundCrystal structure of fatty acid amide hydrolase with small molecule compound
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). Publication Abstract from PubMedFatty 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. 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||