6dxx: Difference between revisions
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==Human N-acylethanolamine-hydrolyzing acid amidase (NAAA) in complex with non-covalent benzothiazole-piperazine inhibitor ARN19702, in presence of Triton X-100== | ==Human N-acylethanolamine-hydrolyzing acid amidase (NAAA) in complex with non-covalent benzothiazole-piperazine inhibitor ARN19702, in presence of Triton X-100== | ||
<StructureSection load='6dxx' size='340' side='right' caption='[[6dxx]], [[Resolution|resolution]] 2.70Å' scene=''> | <StructureSection load='6dxx' size='340' side='right'caption='[[6dxx]], [[Resolution|resolution]] 2.70Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6dxx]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DXX OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6dxx]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DXX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DXX 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=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SCN:THIOCYANATE+ION'>SCN</scene>, <scene name='pdbligand=TON:2-{2-[4-(1,1,3,3-TETRAMETHYLBUTYL)PHENOXY]ETHOXY}ETHANOL'>TON</scene>, <scene name='pdbligand=WTF:[2-(ethylsulfonyl)phenyl][(2S)-4-(6-fluoro-1,3-benzothiazol-2-yl)-2-methylpiperazin-1-yl]methanone'>WTF</scene></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7Å</td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <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=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SCN:THIOCYANATE+ION'>SCN</scene>, <scene name='pdbligand=TON:2-{2-[4-(1,1,3,3-TETRAMETHYLBUTYL)PHENOXY]ETHOXY}ETHANOL'>TON</scene>, <scene name='pdbligand=WTF:[2-(ethylsulfonyl)phenyl][(2S)-4-(6-fluoro-1,3-benzothiazol-2-yl)-2-methylpiperazin-1-yl]methanone'>WTF</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=6dxx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dxx OCA], [https://pdbe.org/6dxx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6dxx RCSB], [https://www.ebi.ac.uk/pdbsum/6dxx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6dxx ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/NAAA_HUMAN NAAA_HUMAN] Degrades bioactive fatty acid amides to their corresponding acids, with the following preference: N-palmitoylethanolamine > N-myristoylethanolamine > N-lauroylethanolamine = N-stearoylethanolamine > N-arachidonoylethanolamine > N-oleoylethanolamine. Also exhibits weak hydrolytic activity against the ceramides N-lauroylsphingosine and N-palmitoylsphingosine.<ref>PMID:15655246</ref> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Palmitoylethanolamide is a bioactive lipid that strongly alleviates pain and inflammation in animal models and in humans. Its signaling activity is terminated through degradation by N-acylethanolamine acid amidase (NAAA), a cysteine hydrolase expressed at high levels in immune cells. Pharmacological inhibitors of NAAA activity exert profound analgesic and antiinflammatory effects in rodent models, pointing to this protein as a potential target for therapeutic drug discovery. To facilitate these efforts and to better understand the molecular mechanism of action of NAAA, we determined crystal structures of this enzyme in various activation states and in complex with several ligands, including both a covalent and a reversible inhibitor. Self-proteolysis exposes the otherwise buried active site of NAAA to allow catalysis. Formation of a stable substrate- or inhibitor-binding site appears to be conformationally coupled to the interaction of a pair of hydrophobic helices in the enzyme with lipid membranes, resulting in the creation of a linear hydrophobic cavity near the active site that accommodates the ligand's acyl chain. | |||
Molecular mechanism of activation of the immunoregulatory amidase NAAA.,Gorelik A, Gebai A, Illes K, Piomelli D, Nagar B Proc Natl Acad Sci U S A. 2018 Oct 9. pii: 1811759115. doi:, 10.1073/pnas.1811759115. PMID:30301806<ref>PMID:30301806</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6dxx" style="background-color:#fffaf0;"></div> | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Gebai A]] | ||
[[Category: | [[Category: Gorelik A]] | ||
[[Category: | [[Category: Illes K]] | ||
[[Category: | [[Category: Nagar B]] | ||
[[Category: | [[Category: Piomelli D]] | ||