6o0h: Difference between revisions
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<StructureSection load='6o0h' size='340' side='right'caption='[[6o0h]], [[Resolution|resolution]] 3.67Å' scene=''> | <StructureSection load='6o0h' size='340' side='right'caption='[[6o0h]], [[Resolution|resolution]] 3.67Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6o0h]] is a 4 chain structure. 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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6O0H FirstGlance]. <br> | <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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6O0H FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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='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='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='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'>[http://oca.weizmann.ac.il/oca-docs/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> | <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=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> | ||
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</StructureSection> | </StructureSection> | ||
[[Category: ATP citrate synthase]] | [[Category: ATP citrate synthase]] | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Tong, L]] | [[Category: Tong, L]] | ||
Revision as of 16:43, 10 May 2019
Cryo-EM structure of human ATP-citrate lyase in complex with inhibitor NDI-091143Cryo-EM structure of human ATP-citrate lyase in complex with inhibitor NDI-091143
Structural highlights
Function[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.[1] Publication Abstract from PubMedATP-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[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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