2Q8H

Structure of pyruvate dehydrogenase kinase isoform 1 in complex with dichloroacetate (DCA)

2Q8H の概要

• エントリーDOI: 10.2210/pdb2q8h/pdb
• 関連するPDBエントリー: 2Q8F 2Q8G 2Q8I
• 分子名称: [Pyruvate dehydrogenase [lipoamide]] kinase isozyme 1, POTASSIUM ION, DICHLORO-ACETIC ACID, ... (4 entities in total)
• 機能のキーワード: ghkl atpase/kinase family, pyruvate dehydrogenase complex, mitochondrial kinase, dichroloacetate, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Mitochondrion matrix : Q15118
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 46529.66

構造登録者

Kato, M.,Li, J.,Chuang, J.L.,Chuang, D.T. (登録日: 2007-06-10, 公開日: 2007-07-24, 最終更新日: 2023-08-30)

主引用文献

Kato, M.,Li, J.,Chuang, J.L.,Chuang, D.T.
Distinct Structural Mechanisms for Inhibition of Pyruvate Dehydrogenase Kinase Isoforms by AZD7545, Dichloroacetate, and Radicicol.
Structure, 15:992-1004, 2007

PubMed Abstract: Pyruvate dehydrogenase kinase (PDK) isoforms are molecular switches that downregulate the pyruvate dehydrogenase complex (PDC) by reversible phosphorylation in mitochondria. We have determined structures of human PDK1 or PDK3 bound to the inhibitors AZD7545, dichloroacetate (DCA), and radicicol. We show that the trifluoromethylpropanamide end of AZD7545 projects into the lipoyl-binding pocket of PDK1. This interaction results in inhibition of PDK1 and PDK3 activities by aborting kinase binding to the PDC scaffold. Paradoxically, AZD7545 at saturating concentrations robustly increases scaffold-free PDK3 activity, similar to the inner lipoyl domain. Good DCA density is present in the helix bundle in the N-terminal domain of PDK1. Bound DCA promotes local conformational changes that are communicated to both nucleotide-binding and lipoyl-binding pockets of PDK1, leading to the inactivation of kinase activity. Finally, radicicol inhibits kinase activity by binding directly to the ATP-binding pocket of PDK3, similar to Hsp90 and Topo VI from the same ATPase/kinase superfamily.

PubMed: 17683942
DOI: 10.1016/j.str.2007.07.001

実験手法

X-RAY DIFFRACTION (2 Å)