6O0H

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

  • Classification: ligase/ligase inhibitor
  • Organism(s): Homo sapiens
  • Expression System: Escherichia coli
  • Mutation(s): No 

  • Deposited: 2019-02-16 Released: 2019-04-17 
  • Deposition Author(s): Wei, J., Tong, L.
  • Funding Organization(s): Other private, National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS), Other government

Experimental Data Snapshot

  • Method: ELECTRON MICROSCOPY
  • Resolution: 3.67 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

wwPDB Validation 3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

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

Wei, J.Leit, S.Kuai, J.Therrien, E.Rafi, S.Harwood Jr., H.J.DeLaBarre, B.Tong, L.

(2019) Nature 568: 566-570

  • DOI: 10.1038/s41586-019-1094-6
  • Structures With Same Primary Citation

  • 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 1-5 . The acetyl-CoA product is crucial for the metabolism of fatty acids

    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.


    Organizational Affiliation

    Department of Biological Sciences, Columbia University, New York, NY, USA. ltong@columbia.edu.



Macromolecules

Find similar proteins by: Sequence  |  Structure

Entity ID: 1
MoleculeChainsSequence LengthOrganismDetails
ATP-citrate synthase
A, B, C, D
1116Homo sapiensMutation(s): 0 
Gene Names: ACLY
EC: 2.3.3.8
Find proteins for P53396 (Homo sapiens)
Go to UniProtKB:  P53396
NIH Common Fund Data Resources
PHAROS  P53396
Small Molecules
Ligands 2 Unique
IDChainsName / Formula / InChI Key2D Diagram3D Interactions
LBG
Query on LBG

Download CCD File 
A, B, C, D
methyl 3-chloro-5-[(4,6-difluoro[1,1'-biphenyl]-3-yl)sulfamoyl]-4-hydroxybenzoate
C20 H14 Cl F2 N O5 S
YSTSHUWHIDBZAK-UHFFFAOYSA-N
 Ligand Interaction
ADP
Query on ADP

Download CCD File 
A, B, C, D
ADENOSINE-5'-DIPHOSPHATE
C10 H15 N5 O10 P2
XTWYTFMLZFPYCI-KQYNXXCUSA-N
 Ligand Interaction
Experimental Data & Validation

Experimental Data

  • Method: ELECTRON MICROSCOPY
  • Resolution: 3.67 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data

  • Deposited Date: 2019-02-16 
  • Released Date: 2019-04-17 
  • Deposition Author(s): Wei, J., Tong, L.

Funding OrganizationLocationGrant Number
Other privateUnited StatesNimbus Therapeutics
Other privateUnited StatesSimons Foundation (349247)
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesGM103310
Other governmentUnited StatesNYSTAR

Revision History 

  • Version 1.0: 2019-04-17
    Type: Initial release
  • Version 1.1: 2019-05-08
    Changes: Data collection, Database references
  • Version 1.2: 2020-01-08
    Changes: Author supporting evidence, Data collection