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TitleAn allosteric mechanism for potent inhibition of human ATP-citrate lyase.
Journal, issue, pagesNature, Vol. 568, Issue 7753, Page 566-570, Year 2019
Publish dateApr 3, 2019
AuthorsJia Wei / Silvana Leit / Jun Kuai / Eric Therrien / Salma Rafi / H James Harwood / Byron DeLaBarre / Liang Tong /
PubMed AbstractATP-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. The acetyl-CoA product is crucial for ...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. The acetyl-CoA product is crucial for the metabolism of fatty acids, the biosynthesis of cholesterol, and the acetylation and prenylation of proteins. There has been considerable interest in ACLY as a target for anti-cancer drugs, because many cancer cells depend on its activity for proliferation. ACLY is also a target against dyslipidaemia and hepatic steatosis, with a compound currently in phase 3 clinical trials. Many inhibitors of ACLY have been reported, but most of them have weak activity. 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.
External linksNature / PubMed:30944472
MethodsEM (single particle)
Resolution3.67 - 4.11 Å
Structure data

0567

6o0h

EMDB-0567, PDB-6o0h:
Cryo-EM structure of human ATP-citrate lyase in complex with inhibitor NDI-091143
Method: EM (single particle) / Resolution: 3.67 Å

EMDB-0568:
Cryo-EM 3D map of human ATP-citrate lyase N-terminal segment in complex with inhibitor NDI-091143
Method: EM (single particle) / Resolution: 4.11 Å

Chemicals

ChemComp-LBG:
methyl 3-chloro-5-[(4,6-difluoro[1,1'-biphenyl]-3-yl)sulfamoyl]-4-hydroxybenzoate

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

Source
  • homo sapiens (human)
Keywordsligase/ligase inhibitor / ATP-citrate lyase / LIGASE / ligase-ligase inhibitor complex

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