7WTD

Cryo-EM structure of human pyruvate carboxylase with acetyl-CoA in the intermediate state 1

7WTD の概要

• エントリーDOI: 10.2210/pdb7wtd/pdb
• 関連するPDBエントリー: 7WTA
• EMDBエントリー: 32779
• 分子名称: Pyruvate carboxylase, mitochondrial, ADENOSINE-5'-TRIPHOSPHATE, COENZYME A (3 entities in total)
• 機能のキーワード: pyruvate carboxylase, oncoprotein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 521746.87

構造登録者

Chai, P.,Lan, P.,Wu, J.,Lei, M. (登録日: 2022-02-04, 公開日: 2022-11-09, 最終更新日: 2022-11-16)

主引用文献

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

実験手法

ELECTRON MICROSCOPY (3.9 Å)