3pr0: Difference between revisions

From Proteopedia
Jump to navigation Jump to search
No edit summary
No edit summary
Line 1: Line 1:
==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]] 2.20&Aring;' scene=''>
<StructureSection load='3pr0' size='340' side='right' caption='[[3pr0]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[3pr0]] is a 2 chain structure with sequence from [http://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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3PR0 FirstGlance]. <br>
<table><tr><td colspan='2'>[[3pr0]] 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=3PR0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3PR0 FirstGlance]. <br>
</td></tr><tr id='ligand'><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>
</td></tr><tr id='ligand'><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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2wj1|2wj1]], [[2wj2|2wj2]], [[3k7f|3k7f]], [[3k83|3k83]], [[3k84|3k84]], [[3ppm|3ppm]]</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2wj1|2wj1]], [[2wj2|2wj2]], [[3k7f|3k7f]], [[3k83|3k83]], [[3k84|3k84]], [[3ppm|3ppm]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Faah, faah-1, Faah1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Rattus norvegicus])</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Faah, faah-1, Faah1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Amidase Amidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.1.4 3.5.1.4] </span></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Amidase Amidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.1.4 3.5.1.4] </span></td></tr>
<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=3pr0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3pr0 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3pr0 RCSB], [http://www.ebi.ac.uk/pdbsum/3pr0 PDBsum]</span></td></tr>
<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=3pr0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3pr0 OCA], [http://pdbe.org/3pr0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3pr0 RCSB], [http://www.ebi.ac.uk/pdbsum/3pr0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3pr0 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
Line 19: Line 20:
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, 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 27: Line 29:
</StructureSection>
</StructureSection>
[[Category: Amidase]]
[[Category: Amidase]]
[[Category: Rattus norvegicus]]
[[Category: Buffalo rat]]
[[Category: Boger, D L]]
[[Category: Boger, D L]]
[[Category: Han, G W]]
[[Category: Han, G W]]

Revision as of 12:15, 5 August 2016

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

3pr0 is a 2 chain structure with sequence from Buffalo rat. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:, ,
Gene:Faah, faah-1, Faah1 (Buffalo rat)
Activity:Amidase, with EC number 3.5.1.4
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[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).

Publication Abstract from PubMed

Two 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 Also

References

  1. Mileni M, Garfunkle J, Ezzili C, Cravatt BF, Stevens RC, Boger DL. 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. J Am Chem Soc. 2011 Mar 23;133(11):4092-100. Epub 2011 Feb 28. PMID:21355555 doi:10.1021/ja110877y

3pr0, resolution 2.20Å

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA