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| | <SX load='6o0h' size='340' side='right' viewer='molstar' caption='[[6o0h]], [[Resolution|resolution]] 3.67Å' scene=''> | | <SX load='6o0h' size='340' side='right' viewer='molstar' caption='[[6o0h]], [[Resolution|resolution]] 3.67Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6o0h]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6O0H OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6O0H FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6o0h]] is a 4 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=6O0H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6O0H FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=LBG:methyl+3-chloro-5-[(4,6-difluoro[1,1-biphenyl]-3-yl)sulfamoyl]-4-hydroxybenzoate'>LBG</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.67Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ACLY ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=LBG:methyl+3-chloro-5-[(4,6-difluoro[1,1-biphenyl]-3-yl)sulfamoyl]-4-hydroxybenzoate'>LBG</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/ATP_citrate_synthase ATP citrate synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.3.8 2.3.3.8] </span></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=6o0h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o0h OCA], [https://pdbe.org/6o0h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6o0h RCSB], [https://www.ebi.ac.uk/pdbsum/6o0h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6o0h ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6o0h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o0h OCA], [http://pdbe.org/6o0h PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6o0h RCSB], [http://www.ebi.ac.uk/pdbsum/6o0h PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6o0h ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ACLY_HUMAN ACLY_HUMAN]] ATP citrate-lyase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. Has a central role in de novo lipid synthesis. In nervous tissue it may be involved in the biosynthesis of acetylcholine.<ref>PMID:23932781</ref> | + | [https://www.uniprot.org/uniprot/ACLY_HUMAN ACLY_HUMAN] ATP citrate-lyase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. Has a central role in de novo lipid synthesis. In nervous tissue it may be involved in the biosynthesis of acetylcholine.<ref>PMID:23932781</ref> |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | ATP-citrate lyase (ACLY) is a central metabolic enzyme and catalyses the ATP-dependent conversion of citrate and coenzyme A (CoA) to oxaloacetate and acetyl-CoA(1-5). The acetyl-CoA product is crucial for the metabolism of fatty acids(6,7), the biosynthesis of cholesterol(8), and the acetylation and prenylation of proteins(9,10). There has been considerable interest in ACLY as a target for anti-cancer drugs, because many cancer cells depend on its activity for proliferation(2,5,11). ACLY is also a target against dyslipidaemia and hepatic steatosis, with a compound currently in phase 3 clinical trials(4,5). Many inhibitors of ACLY have been reported, but most of them have weak activity(5). Here we report the development of a series of low nanomolar, small-molecule inhibitors of human ACLY. We have also determined the structure of the full-length human ACLY homo-tetramer in complex with one of these inhibitors (NDI-091143) by cryo-electron microscopy, which reveals an unexpected mechanism of inhibition. The compound is located in an allosteric, mostly hydrophobic cavity next to the citrate-binding site, and requires extensive conformational changes in the enzyme that indirectly disrupt citrate binding. The observed binding mode is supported by and explains the structure-activity relationships of these compounds. This allosteric site greatly enhances the 'druggability' of ACLY and represents an attractive target for the development of new ACLY inhibitors.
| + | |
| | | | |
| - | An allosteric mechanism for potent inhibition of human ATP-citrate lyase.,Wei J, Leit S, Kuai J, Therrien E, Rafi S, Harwood HJ Jr, DeLaBarre B, Tong L Nature. 2019 Apr 3. pii: 10.1038/s41586-019-1094-6. doi:, 10.1038/s41586-019-1094-6. PMID:30944472<ref>PMID:30944472</ref>
| + | ==See Also== |
| - | | + | *[[ATP-citrate synthase 3D structures|ATP-citrate synthase 3D structures]] |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 6o0h" style="background-color:#fffaf0;"></div>
| + | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </SX> | | </SX> |
| - | [[Category: ATP citrate synthase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Tong, L]] | + | [[Category: Tong L]] |
| - | [[Category: Wei, J]] | + | [[Category: Wei J]] |
| - | [[Category: Atp-citrate lyase]]
| + | |
| - | [[Category: Ligase]]
| + | |
| - | [[Category: Ligase-ligase inhibitor complex]]
| + | |
