View source for 2wj2


==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-ketooxazole==
<StructureSection load='2wj2' size='340' side='right'caption='[[2wj2]], [[Resolution|resolution]] 2.55&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2wj2]] 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=2WJ2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2WJ2 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]] 2.55&#8491;</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=OL1:7-PHENYL-1-(5-PYRIDIN-2-YL-1,3-OXAZOL-2-YL)HEPTANE-1,1-DIOL'>OL1</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=2wj2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wj2 OCA], [https://pdbe.org/2wj2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2wj2 RCSB], [https://www.ebi.ac.uk/pdbsum/2wj2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2wj2 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/wj/2wj2_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.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=2wj2 ConSurf].
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<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The 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<ref>PMID:19722626</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 2wj2" 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: Boger DL]]
[[Category: Cravatt BF]]
[[Category: DeMartino JK]]
[[Category: Garfunkle J]]
[[Category: Mileni M]]
[[Category: Stevens RC]]