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

6o0h is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:,
Gene:ACLY (HUMAN)
Activity:ATP citrate synthase, with EC number 2.3.3.8
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 PubMed

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(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

  1. Lin R, Tao R, Gao X, Li T, Zhou X, Guan KL, Xiong Y, Lei QY. Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth. Mol Cell. 2013 Aug 22;51(4):506-18. doi: 10.1016/j.molcel.2013.07.002. Epub 2013 , Aug 8. PMID:23932781 doi:http://dx.doi.org/10.1016/j.molcel.2013.07.002
  2. Wei J, Leit S, Kuai J, Therrien E, Rafi S, Harwood HJ Jr, DeLaBarre B, Tong L. An allosteric mechanism for potent inhibition of human ATP-citrate lyase. Nature. 2019 Apr 3. pii: 10.1038/s41586-019-1094-6. doi:, 10.1038/s41586-019-1094-6. PMID:30944472 doi:http://dx.doi.org/10.1038/s41586-019-1094-6

6o0h, resolution 3.67Å

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