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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== | ==Crystal Structure of a Covalently Bound alpha-Ketoheterocycle Inhibitor (Phenhexyl/Oxadiazole/Pyridine) to a Humanized Variant of Fatty Acid Amide Hydrolase== | ||
<StructureSection load='3pr0' size='340' side='right' caption='[[3pr0]], [[Resolution|resolution]] 2.20Å' scene=''> | <StructureSection load='3pr0' size='340' side='right'caption='[[3pr0]], [[Resolution|resolution]] 2.20Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3pr0]] is a 2 chain structure with sequence from [ | <table><tr><td colspan='2'>[[3pr0]] 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=3PR0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3PR0 FirstGlance]. <br> | ||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=JG2:7-PHENYL-1-[5-(PYRIDIN-2-YL)-1,3,4-OXADIAZOL-2-YL]HEPTANE-1,1-DIOL'>JG2</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2Å</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=JG2:7-PHENYL-1-[5-(PYRIDIN-2-YL)-1,3,4-OXADIAZOL-2-YL]HEPTANE-1,1-DIOL'>JG2</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></td></tr> | |||
<tr | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3pr0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3pr0 OCA], [https://pdbe.org/3pr0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3pr0 RCSB], [https://www.ebi.ac.uk/pdbsum/3pr0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3pr0 ProSAT]</span></td></tr> | ||
</table> | |||
== Function == | |||
<table> | [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;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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Fluoride-mediated capture of a noncovalent bound state of a reversible covalent enzyme inhibitor: X-ray crystallographic analysis of an exceptionally potent alpha-ketoheterocycle inhibitor of fatty acid amide hydrolase.,Mileni M, Garfunkle J, Ezzili C, Cravatt BF, Stevens RC, Boger DL J Am Chem Soc. 2011 Mar 23;133(11):4092-100. Epub 2011 Feb 28. PMID:21355555<ref>PMID:21355555</ref> | Fluoride-mediated capture of a noncovalent bound state of a reversible covalent enzyme inhibitor: X-ray crystallographic analysis of an exceptionally potent alpha-ketoheterocycle inhibitor of fatty acid amide hydrolase.,Mileni M, Garfunkle J, Ezzili C, Cravatt BF, Stevens RC, Boger DL J Am Chem Soc. 2011 Mar 23;133(11):4092-100. Epub 2011 Feb 28. PMID:21355555<ref>PMID:21355555</ref> | ||
From | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 3pr0" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
| Line 24: | Line 26: | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Rattus norvegicus]] | [[Category: Rattus norvegicus]] | ||
[[Category: Boger | [[Category: Boger DL]] | ||
[[Category: Han | [[Category: Han GW]] | ||
[[Category: Mileni | [[Category: Mileni M]] | ||
[[Category: Stevens | [[Category: Stevens RC]] | ||
Latest revision as of 12:59, 6 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 PubMedTwo cocrystal X-ray structures of the exceptionally potent alpha-ketoheterocycle inhibitor 1 (K(i) = 290 pM) bound to a humanized variant of rat fatty acid amide hydrolase (FAAH) are disclosed, representing noncovalently and covalently bound states of the same inhibitor with the enzyme. Key to securing the structure of the noncovalently bound state of the inhibitor was the inclusion of fluoride ion in the crystallization conditions that is proposed to bind the oxyanion hole precluding inhibitor covalent adduct formation with stabilization of the tetrahedral hemiketal. This permitted the opportunity to detect important noncovalent interactions stabilizing the binding of the inhibitor within the FAAH active site independent of the covalent reaction. Remarkably, noncovalently bound 1 in the presence of fluoride appears to capture the active site in the same "in action" state with the three catalytic residues Ser241-Ser217-Lys142 occupying essentially identical positions observed in the covalently bound structure of 1, suggesting that this technique of introducing fluoride may have important applications in structural studies beyond inhibiting substrate or inhibitor oxyanion hole binding. Key insights to emerge from the studies include the observations that noncovalently bound 1 binds in its ketone (not gem diol) form, that the terminal phenyl group in the acyl side chain of the inhibitor serves as the key anchoring interaction overriding the intricate polar interactions in the cytosolic port, and that the role of the central activating heterocycle is dominated by its intrinsic electron-withdrawing properties. These two structures are also briefly compared with five X-ray structures of alpha-ketoheterocycle-based inhibitors bound to FAAH recently disclosed. Fluoride-mediated capture of a noncovalent bound state of a reversible covalent enzyme inhibitor: X-ray crystallographic analysis of an exceptionally potent alpha-ketoheterocycle inhibitor of fatty acid amide hydrolase.,Mileni M, Garfunkle J, Ezzili C, Cravatt BF, Stevens RC, Boger DL J Am Chem Soc. 2011 Mar 23;133(11):4092-100. Epub 2011 Feb 28. PMID:21355555[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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