Asset Details
Do you wish to reserve the book?
An allosteric mechanism for potent inhibition of human ATP-citrate lyase
Hey, we have placed the reservation for you!
By the way, why not check out events that you can attend while you pick your title.
Oops! Something went wrong.
Looks like we were not able to place the reservation. Kindly try again later.
Are you sure you want to remove the book from the shelf?
An allosteric mechanism for potent inhibition of human ATP-citrate lyase
Do you wish to request the book?
An allosteric mechanism for potent inhibition of human ATP-citrate lyase
Please be aware that the book you have requested cannot be checked out. If you would like to checkout this book, you can reserve another copy
We have requested the book for you!
Your request is successful and it will be processed during the Library working hours. Please check the status of your request in My Requests.
Oops! Something went wrong.
Looks like we were not able to place your request. Kindly try again later.
Journal Article
An allosteric mechanism for potent inhibition of human ATP-citrate lyase
2019
Overview
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.
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 49
/ 82/103
/ 82/16
/ 82/80
/ 82/83
/ Adenosine Diphosphate - metabolism
/ Allosteric Regulation - drug effects
/ Analysis
/ 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
/ Benzyl Compounds - chemistry
/ Benzyl Compounds - pharmacology
/ Binding Sites - drug effects
/ Enzyme Inhibitors - chemistry
/ Enzyme Inhibitors - pharmacology
/ Enzymes
/ Humanities and Social Sciences
/ Humans
/ Hydrophobic and Hydrophilic Interactions
/ Letter
/ Ligands
/ Lyases
/ Science
