1X7Z

Crystal structure of the human mitochondrial branched-chain alpha-ketoacid dehydrogenase

1X7Z の概要

• エントリーDOI: 10.2210/pdb1x7z/pdb
• 関連するPDBエントリー: 1U5B 1X7W 1X7X 1X7Y 1X80
• 分子名称: 2-oxoisovalerate dehydrogenase alpha subunit, 2-oxoisovalerate dehydrogenase beta subunit, POTASSIUM ION, ... (8 entities in total)
• 機能のキーワード: oxidoreductase, ketoacid dehydrogenase, branched-chain, multi-enzyme complex, acylation, oxidative decarboxylation maple syrup urine disease, thiamin diphosphate, phosphorylation, flavoprotein
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Mitochondrion matrix: P12694 P21953
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 84187.37

構造登録者

Wynn, R.M.,Kato, M.,Machius, M.,Chuang, J.L.,Li, J.,Tomchick, D.R.,Chuang, D.T. (登録日: 2004-08-16, 公開日: 2004-11-23, 最終更新日: 2023-08-23)

主引用文献

Wynn, R.M.,Kato, M.,Machius, M.,Chuang, J.L.,Li, J.,Tomchick, D.R.,Chuang, D.T.
Molecular mechanism for regulation of the human mitochondrial branched-chain alpha-ketoacid dehydrogenase complex by phosphorylation
Structure, 12:2185-2196, 2004

PubMed Abstract: The human mitochondrial branched-chain alpha-ketoacid dehydrogenase complex (BCKDC) is a 4 MDa macromolecular machine comprising three catalytic components (E1b, E2b, and E3), a kinase, and a phosphatase. The BCKDC overall activity is tightly regulated by phosphorylation in response to hormonal and dietary stimuli. We report that phosphorylation of Ser292-alpha in the E1b active site channel results in an order-to-disorder transition of the conserved phosphorylation loop carrying the phosphoryl serine. The conformational change is triggered by steric clashes of the phosphoryl group with invariant His291-alpha that serves as an indispensable anchor for the phosphorylation loop through bound thiamin diphosphate. Phosphorylation of Ser292-alpha does not severely impede the E1b-dependent decarboxylation of alpha-ketoacids. However, the disordered loop conformation prevents phosphorylated E1b from binding the E2b lipoyl-bearing domain, which effectively shuts off the E1b-catalyzed reductive acylation reaction and therefore completely inactivates BCKDC. This mechanism provides a paradigm for regulation of mitochondrial alpha-ketoacid dehydrogenase complexes by phosphorylation.

PubMed: 15576032
DOI: 10.1016/j.str.2004.09.013

実験手法

X-RAY DIFFRACTION (1.72 Å)