3EXH

Crystal structure of the pyruvate dehydrogenase (E1p) component of human pyruvate dehydrogenase complex

3EXH の概要

• エントリーDOI: 10.2210/pdb3exh/pdb
• 関連するPDBエントリー: 3EXE 3EXF 3EXG 3EXI
• 分子名称: Pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial, Pyruvate dehydrogenase E1 component subunit beta, mitochondrial, MANGANESE (II) ION, ... (8 entities in total)
• 機能のキーワード: heterotetramer; thiamine diphosphate-dependent enzyme; disease mutation; glycolysis; leigh syndrome; mitochondrion; oxidoreductase; phosphoprotein; alternative splicing; polymorphism; pyruvate; thiamine pyrophosphate; transit peptide, oxidoreductase
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Mitochondrion matrix: P08559 P11177 P08559
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 316673.15

構造登録者

Kato, M.,Wynn, R.M.,Chuang, J.L.,Tso, S.-C.,Machius, M.,Li, J.,Chuang, D.T. (登録日: 2008-10-16, 公開日: 2008-11-25, 最終更新日: 2023-12-27)

主引用文献

Kato, M.,Wynn, R.M.,Chuang, J.L.,Tso, S.C.,Machius, M.,Li, J.,Chuang, D.T.
Structural basis for inactivation of the human pyruvate dehydrogenase complex by phosphorylation: role of disordered phosphorylation loops.
Structure, 16:1849-1859, 2008

PubMed Abstract: We report the crystal structures of the phosporylated pyruvate dehydrogenase (E1p) component of the human pyruvate dehydrogenase complex (PDC). The complete phosphorylation at Ser264-alpha (site 1) of a variant E1p protein was achieved using robust pyruvate dehydrogenase kinase 4 free of the PDC core. We show that unlike its unmodified counterpart, the presence of a phosphoryl group at Ser264-alpha prevents the cofactor thiamine diphosphate-induced ordering of the two loops carrying the three phosphorylation sites. The disordering of these phosphorylation loops is caused by a previously unrecognized steric clash between the phosphoryl group at site 1 and a nearby Ser266-alpha, which nullifies a hydrogen-bonding network essential for maintaining the loop conformations. The disordered phosphorylation loops impede the binding of lipoyl domains of the PDC core to E1p, negating the reductive acetylation step. This results in the disruption of the substrate channeling in the PDC, leading to the inactivation of this catalytic machine.

PubMed: 19081061
DOI: 10.1016/j.str.2008.10.010

実験手法

X-RAY DIFFRACTION (2.444 Å)