An allosteric mechanism for potent inhibition of human ATP-citrate lyase

Nature. 2019 Apr;568(7753):566-570. doi: 10.1038/s41586-019-1094-6. Epub 2019 Apr 3.

Abstract

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-CoA1-5. The acetyl-CoA product is crucial for the metabolism of fatty acids6,7, the biosynthesis of cholesterol8, and the acetylation and prenylation of proteins9,10. There has been considerable interest in ACLY as a target for anti-cancer drugs, because many cancer cells depend on its activity for proliferation2,5,11. ACLY is also a target against dyslipidaemia and hepatic steatosis, with a compound currently in phase 3 clinical trials4,5. Many inhibitors of ACLY have been reported, but most of them have weak activity5. 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.

MeSH terms

  • ATP Citrate (pro-S)-Lyase / antagonists & inhibitors*
  • ATP Citrate (pro-S)-Lyase / chemistry
  • ATP Citrate (pro-S)-Lyase / metabolism
  • ATP Citrate (pro-S)-Lyase / ultrastructure*
  • Adenosine Diphosphate / metabolism
  • Allosteric Regulation / drug effects
  • Benzyl Compounds / chemistry
  • Benzyl Compounds / pharmacology*
  • Binding Sites / drug effects
  • Citric Acid / metabolism
  • Cryoelectron Microscopy*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Models, Molecular
  • Protein Domains
  • Protein Multimerization
  • Structure-Activity Relationship

Substances

  • Benzyl Compounds
  • Enzyme Inhibitors
  • NDI-091143
  • Citric Acid
  • Adenosine Diphosphate
  • ATP Citrate (pro-S)-Lyase