5sym: Difference between revisions
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==Cocrystal structure of the human acyl protein thioesterase 1 with an isoform-selective inhibitor, ML348== | ==Cocrystal structure of the human acyl protein thioesterase 1 with an isoform-selective inhibitor, ML348== | ||
<StructureSection load='5sym' size='340' side='right' caption='[[5sym]], [[Resolution|resolution]] 1.55Å' scene=''> | <StructureSection load='5sym' size='340' side='right'caption='[[5sym]], [[Resolution|resolution]] 1.55Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5sym]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5SYM OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[5sym]] is a 2 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=5SYM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5SYM FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=71Q:N-[2-CHLORO-5-(TRIFLUOROMETHYL)PHENYL]-2-[4-(FURAN-2-CARBONYL)PIPERAZIN-1-YL]ACETAMIDE'>71Q</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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]] 1.55Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=71Q:N-[2-CHLORO-5-(TRIFLUOROMETHYL)PHENYL]-2-[4-(FURAN-2-CARBONYL)PIPERAZIN-1-YL]ACETAMIDE'>71Q</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5sym FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5sym OCA], [https://pdbe.org/5sym PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5sym RCSB], [https://www.ebi.ac.uk/pdbsum/5sym PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5sym ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/LYPA1_HUMAN LYPA1_HUMAN] Hydrolyzes fatty acids from S-acylated cysteine residues in proteins such as trimeric G alpha proteins or HRAS. Has depalmitoylating activity and also low lysophospholipase activity.<ref>PMID:20418879</ref> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 19: | Line 19: | ||
</div> | </div> | ||
<div class="pdbe-citations 5sym" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 5sym" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Thioesterase 3D structures|Thioesterase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Labby KJ]] | ||
[[Category: | [[Category: Martin BR]] | ||
[[Category: | [[Category: Meagher JL]] | ||
[[Category: | [[Category: Stuckey JA]] | ||
[[Category: | [[Category: Won SJ]] | ||
Latest revision as of 15:51, 4 October 2023
Cocrystal structure of the human acyl protein thioesterase 1 with an isoform-selective inhibitor, ML348Cocrystal structure of the human acyl protein thioesterase 1 with an isoform-selective inhibitor, ML348
Structural highlights
FunctionLYPA1_HUMAN Hydrolyzes fatty acids from S-acylated cysteine residues in proteins such as trimeric G alpha proteins or HRAS. Has depalmitoylating activity and also low lysophospholipase activity.[1] Publication Abstract from PubMedPost-translational S-palmitoylation directs the trafficking and membrane localization of hundreds of cellular proteins, often involving a coordinated palmitoylation cycle that requires both protein acyl transferases (PATs) and acyl protein thioesterases (APTs) to actively redistribute S-palmitoylated proteins toward different cellular membrane compartments. This process is necessary for the trafficking and oncogenic signaling of S-palmitoylated Ras isoforms, and potentially many peripheral membrane proteins. The depalmitoylating enzymes APT1 and APT2 are separately conserved in all vertebrates, suggesting unique functional roles for each enzyme. The recent discovery of the APT isoform-selective inhibitors ML348 and ML349 has opened new possibilities to probe the function of each enzyme, yet it remains unclear how each inhibitor achieves orthogonal inhibition. Herein, we report the high-resolution structure of human APT2 in complex with ML349 (1.64 A), as well as the complementary structure of human APT1 bound to ML348 (1.55 A). Although the overall peptide backbone structures are nearly identical, each inhibitor adopts a distinct conformation within each active site. In APT1, the trifluoromethyl group of ML348 is positioned above the catalytic triad, but in APT2, the sulfonyl group of ML349 forms hydrogen bonds with active site resident waters to indirectly engage the catalytic triad and oxyanion hole. Reciprocal mutagenesis and activity profiling revealed several differing residues surrounding the active site that serve as critical gatekeepers for isoform accessibility and dynamics. Structural and biochemical analysis suggests the inhibitors occupy a putative acyl-binding region, establishing the mechanism for isoform-specific inhibition, hydrolysis of acyl substrates, and structural orthogonality important for future probe development. Molecular Mechanism for Isoform-Selective Inhibition of Acyl Protein Thioesterases 1 and 2 (APT1 and APT2).,Won SJ, Davda D, Labby KJ, Hwang SY, Pricer R, Majmudar JD, Armacost KA, Rodriguez LA, Rodriguez CL, Chong FS, Torossian KA, Palakurthi J, Hur ES, Meagher JL, Brooks CL 3rd, Stuckey JA, Martin BR ACS Chem Biol. 2016 Oct 31. PMID:27748579[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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