6O0H

Cryo-EM structure of human ATP-citrate lyase in complex with inhibitor NDI-091143

Summary for 6O0H

• Entry DOI: 10.2210/pdb6o0h/pdb
• EMDB information: 0567 0568
• Descriptor: ATP-citrate synthase, methyl 3-chloro-5-[(4,6-difluoro[1,1'-biphenyl]-3-yl)sulfamoyl]-4-hydroxybenzoate, ADENOSINE-5'-DIPHOSPHATE (3 entities in total)
• Functional Keywords: atp-citrate lyase, ligase, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 494672.59

Authors

Wei, J.,Tong, L. (deposition date: 2019-02-16, release date: 2019-04-17, Last modification date: 2024-03-20)

Primary citation

Wei, J.,Leit, S.,Kuai, J.,Therrien, E.,Rafi, S.,Harwood Jr., H.J.,DeLaBarre, B.,Tong, L.
An allosteric mechanism for potent inhibition of human ATP-citrate lyase.
Nature, 568:566-570, 2019

PubMed 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-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.

PubMed: 30944472
DOI: 10.1038/s41586-019-1094-6

Experimental method

ELECTRON MICROSCOPY (3.67 Å)