|Entry||Database: EMDB / ID: EMD-0568|
|Title||Cryo-EM 3D map of human ATP-citrate lyase N-terminal segment in complex with inhibitor NDI-091143|
|Source||Homo sapiens (human)|
|Method||single particle reconstruction / cryo EM / Resolution: 4.11 Å|
|Authors||Wei J / Tong L|
|Citation||Journal: Nature / Year: 2019|
Title: An allosteric mechanism for potent inhibition of human ATP-citrate lyase.
Authors: Jia Wei / Silvana Leit / Jun Kuai / Eric Therrien / Salma Rafi / H James Harwood / Byron DeLaBarre / Liang Tong /
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 ...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.
|Date||Deposition: Feb 16, 2019 / Header (metadata) release: Mar 13, 2019 / Map release: May 1, 2019 / Update: May 8, 2019|
|Structure viewer||EM map: |
Downloads & links
|File||Download / File: emd_0568.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)|
|Projections & slices|
Images are generated by Spider.
|Voxel size||X=Y=Z: 1.0605 Å|
|Symmetry||Space group: 1|
CCP4 map header:
-Entire protein-inhibitor complex
|Entire||Name: protein-inhibitor complex / Number of components: 1|
-Component #1: protein, protein-inhibitor complex
|Protein||Name: protein-inhibitor complex / Recombinant expression: No|
|Source||Species: Homo sapiens (human)|
|Source (engineered)||Expression System: Escherichia coli (E. coli) / Strain: BL21 STAR|
|Specimen||Specimen state: Particle / Method: cryo EM|
|Sample solution||Specimen conc.: 4.7 mg/mL / pH: 7.5|
|Vitrification||Instrument: FEI VITROBOT MARK II / Cryogen name: ETHANE / Temperature: 295 K / Humidity: 100 %|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Imaging||Microscope: FEI TITAN KRIOS|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 71 e/Å2 / Illumination mode: FLOOD BEAM|
|Lens||Magnification: 130000.0 X (nominal) / Cs: 2.7 mm / Imaging mode: BRIGHT FIELD / Defocus: -0.8 - -2.0 nm|
|Specimen Holder||Model: FEI TITAN KRIOS AUTOGRID HOLDER|
|Camera||Detector: GATAN K2 SUMMIT (4k x 4k)|
|Image acquisition||Number of digital images: 2803|
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