EMD-32774

Single-particle
3.9 Å
EMD-32774 Deposition: 04/02/2022
Map released: 09/11/2022
Last modified: 16/11/2022
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-32774

PC-(acetyl-CoA) (12.5uM)

EMD-32774

Single-particle
3.9 Å
EMD-32774 Deposition: 04/02/2022
Map released: 09/11/2022
Last modified: 16/11/2022
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens
Sample: PC

Deposition Authors: Chai P , Lan P, Wu J, Lei M
Mechanistic insight into allosteric activation of human pyruvate carboxylase by acetyl-CoA.
Chai P , Lan P, Li S, Yao D, Chang C, Cao M, Shen Y, Ge S, Wu J, Lei M, Fan X
(2022) Mol Cell , 82 , 4116 - 4130.e6
PUBMED: 36283412
DOI: doi:10.1016/j.molcel.2022.09.033
ISSN: 1097-2765
ASTM: MOCEFL
Abstract:
Pyruvate carboxylase (PC) catalyzes the two-step carboxylation of pyruvate to produce oxaloacetate, playing a key role in the maintenance of metabolic homeostasis in cells. Given its involvement in multiple diseases, PC has been regarded as a potential therapeutic target for obesity, diabetes, and cancer. Albeit acetyl-CoA has been recognized as the allosteric regulator of PC for over 60 years, the underlying mechanism of how acetyl-CoA induces PC activation remains enigmatic. Herein, by using time-resolved cryo-electron microscopy, we have captured the snapshots of PC transitional states during its catalytic cycle. These structures and the biochemical studies reveal that acetyl-CoA stabilizes PC in a catalytically competent conformation, which triggers a cascade of events, including ATP hydrolysis and the long-distance communication between the two reactive centers. These findings provide an integrated picture for PC catalysis and unveil the unique allosteric mechanism of acetyl-CoA in an essential biochemical reaction in all kingdoms of life.