• DOI:10.1038/s41586-019-1094-6
• Corpus ID: 93000843

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

@article{Wei2019AnAM,
  title={An allosteric mechanism for potent inhibition of human ATP-citrate lyase},
  author={Jia Wei and Silvana M. Leit and Jun Kuai and Eric Therrien and Salma Rafi and Harold James Harwood and B. Delabarre and Liang Tong},
  journal={Nature},
  year={2019},
  volume={568},
  pages={566-570}
}

• Jia Wei, S. Leit, +5 authors L. Tong
• Published 1 April 2019
• Biology, Chemistry
• Nature

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.The structure of human ATP-citrate lyase, in complex with a newly developed small-molecule inhibitor, shows extensive conformational changes that reveal an allosteric site for the inhibitor to bind and indirectly compete with the citrate substrate.