4j5p: Difference between revisions
New page: '''Unreleased structure''' The entry 4j5p is ON HOLD Authors: Otrubova, K., Brown, M., McCormick, M.S., Han, G.W., O'Neal, S.T., Cravatt, B.F., Stevens, R.C., Lichtman, A.H., Boger, D.L... |
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==Crystal Structure of a Covalently Bound alpha-Ketoheterocycle Inhibitor (Phenhexyl/Oxadiazole/Pyridine) to a Humanized Variant of Fatty Acid Amide Hydrolase== | |||
<StructureSection load='4j5p' size='340' side='right'caption='[[4j5p]], [[Resolution|resolution]] 2.30Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4j5p]] 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=4J5P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4J5P 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]] 2.3Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BR1:(1S)-1-{5-[5-(BROMOMETHYL)PYRIDIN-2-YL]-1,3-OXAZOL-2-YL}-7-PHENYLHEPTAN-1-OL'>BR1</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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=4j5p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4j5p OCA], [https://pdbe.org/4j5p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4j5p RCSB], [https://www.ebi.ac.uk/pdbsum/4j5p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4j5p 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 == | |||
The design and characterization of alpha-ketoheterocycle fatty acid amide hydrolase (FAAH) inhibitors are disclosed that additionally and irreversibly target a cysteine (Cys269) found in the enzyme cytosolic port while maintaining the reversible covalent Ser241 attachment responsible for their rapid and initially reversible enzyme inhibition. Two alpha-ketooxazoles (3 and 4) containing strategically placed electrophiles at the C5 position of the pyridyl substituent of 2 (OL-135) were prepared and examined as inhibitors of FAAH. Consistent with the observed time-dependent noncompetitive inhibition, the cocrystal X-ray structure of 3 bound to a humanized variant of rat FAAH revealed that 3 was not only covalently bound to the active site catalytic nucleophile Ser241 as a deprotonated hemiketal, but also to Cys269 through the pyridyl C5-substituent, thus providing an inhibitor with dual covalent attachment in the enzyme active site. In vivo characterization of the prototypical inhibitors in mice demonstrates that they raise endogenous brain levels of FAAH substrates to a greater extent and for a much longer duration (>6 h) than the reversible inhibitor 2, indicating that the inhibitors accumulate and persist in the brain to completely inhibit FAAH for a prolonged period. Consistent with this behavior and the targeted irreversible enzyme inhibition, 3 reversed cold allodynia in the chronic constriction injury model of neuropathic pain in mice for a sustained period (>6 h) beyond that observed with the reversible inhibitor 2, providing effects that were unchanged over the 1-6 h time course monitored. | |||
Rational design of Fatty Acid amide hydrolase inhibitors that act by covalently bonding to two active site residues.,Otrubova K, Brown M, McCormick MS, Han GW, O'Neal ST, Cravatt BF, Stevens RC, Lichtman AH, Boger DL J Am Chem Soc. 2013 Apr 24;135(16):6289-99. doi: 10.1021/ja4014997. Epub 2013 Apr, 12. PMID:23581831<ref>PMID:23581831</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4j5p" 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: Brown M]] | |||
[[Category: Cravatt BF]] | |||
[[Category: Han GW]] | |||
[[Category: Lichtman AH]] | |||
[[Category: McCormick MS]] | |||
[[Category: O'Neal ST]] | |||
[[Category: Otrubova K]] | |||
[[Category: Stevens RC]] | |||
Latest revision as of 18:36, 20 September 2023
Crystal Structure of a Covalently Bound alpha-Ketoheterocycle Inhibitor (Phenhexyl/Oxadiazole/Pyridine) to a Humanized Variant of Fatty Acid Amide HydrolaseCrystal Structure of a Covalently Bound alpha-Ketoheterocycle Inhibitor (Phenhexyl/Oxadiazole/Pyridine) 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). Publication Abstract from PubMedThe design and characterization of alpha-ketoheterocycle fatty acid amide hydrolase (FAAH) inhibitors are disclosed that additionally and irreversibly target a cysteine (Cys269) found in the enzyme cytosolic port while maintaining the reversible covalent Ser241 attachment responsible for their rapid and initially reversible enzyme inhibition. Two alpha-ketooxazoles (3 and 4) containing strategically placed electrophiles at the C5 position of the pyridyl substituent of 2 (OL-135) were prepared and examined as inhibitors of FAAH. Consistent with the observed time-dependent noncompetitive inhibition, the cocrystal X-ray structure of 3 bound to a humanized variant of rat FAAH revealed that 3 was not only covalently bound to the active site catalytic nucleophile Ser241 as a deprotonated hemiketal, but also to Cys269 through the pyridyl C5-substituent, thus providing an inhibitor with dual covalent attachment in the enzyme active site. In vivo characterization of the prototypical inhibitors in mice demonstrates that they raise endogenous brain levels of FAAH substrates to a greater extent and for a much longer duration (>6 h) than the reversible inhibitor 2, indicating that the inhibitors accumulate and persist in the brain to completely inhibit FAAH for a prolonged period. Consistent with this behavior and the targeted irreversible enzyme inhibition, 3 reversed cold allodynia in the chronic constriction injury model of neuropathic pain in mice for a sustained period (>6 h) beyond that observed with the reversible inhibitor 2, providing effects that were unchanged over the 1-6 h time course monitored. Rational design of Fatty Acid amide hydrolase inhibitors that act by covalently bonding to two active site residues.,Otrubova K, Brown M, McCormick MS, Han GW, O'Neal ST, Cravatt BF, Stevens RC, Lichtman AH, Boger DL J Am Chem Soc. 2013 Apr 24;135(16):6289-99. doi: 10.1021/ja4014997. Epub 2013 Apr, 12. PMID:23581831[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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