7WTC
Cryo-EM structure of human pyruvate carboxylase with acetyl-CoA in the ground state
Summary for 7WTC
Entry DOI | 10.2210/pdb7wtc/pdb |
Related | 7WTA |
EMDB information | 32778 |
Descriptor | Pyruvate carboxylase, mitochondrial, 5-(HEXAHYDRO-2-OXO-1H-THIENO[3,4-D]IMIDAZOL-6-YL)PENTANAL, ACETYL COENZYME *A (3 entities in total) |
Functional Keywords | pyruvate carboxylase, oncoprotein |
Biological source | Homo sapiens (human) |
Total number of polymer chains | 4 |
Total formula weight | 521729.82 |
Authors | |
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 Cited by 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: 36283412DOI: 10.1016/j.molcel.2022.09.033 PDB entries with the same primary citation |
Experimental method | ELECTRON MICROSCOPY (4 Å) |
Structure validation
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