7WTB

Cryo-EM structure of human pyruvate carboxylase with acetyl-CoA

Summary for 7WTB

• Entry DOI: 10.2210/pdb7wtb/pdb
• Related: 7WTA
• EMDB information: 32775
• Descriptor: Pyruvate carboxylase, mitochondrial, 5-(HEXAHYDRO-2-OXO-1H-THIENO[3,4-D]IMIDAZOL-6-YL)PENTANAL, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, ... (4 entities in total)
• Functional Keywords: pyruvate carboxylase, oncoprotein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 522742.21

Authors

Chai, P.,Lan, P.,Wu, J.,Lei, M. (deposition date: 2022-02-04, release date: 2022-11-09, Last modification date: 2022-11-16)

Primary citation

Chai, P.,Lan, P.,Li, S.,Yao, D.,Chang, C.,Cao, M.,Shen, Y.,Ge, S.,Wu, J.,Lei, M.,Fan, X.
Mechanistic insight into allosteric activation of human pyruvate carboxylase by acetyl-CoA.
Mol.Cell, 82:4116-4130.e6, 2022

PubMed 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.

PubMed: 36283412
DOI: 10.1016/j.molcel.2022.09.033

Experimental method

ELECTRON MICROSCOPY (3.7 Å)