2ZDX

Inhibitor-bound structures of human pyruvate dehydrogenase kinase 4

2ZDX の概要

• エントリーDOI: 10.2210/pdb2zdx/pdb
• 関連するPDBエントリー: 2ZDY
• 分子名称: Pyruvate dehydrogenase kinase isozyme 4, 4-[4-(4-methoxyphenyl)-5-methyl-1H-pyrazol-3-yl]benzene-1,3-diol (3 entities in total)
• 機能のキーワード: pdk4, kinase, atp-binding, inhibitor, carbohydrate metabolism, glucose metabolism, mitochondrion, phosphoprotein, transferase, transit peptide
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Mitochondrion matrix: Q16654
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 90134.63

構造登録者

Kawamoto, M.,Shiromizu, I.,Kukimoto-niino, M.,Tokmakov, A.,Terada, T.,Shirouzu, M.,Matsusue, T.,Yokoyama, S. (登録日: 2007-11-30, 公開日: 2008-12-09, 最終更新日: 2023-11-01)

主引用文献

Kukimoto-Niino, M.,Tokmakov, A.,Terada, T.,Ohbayashi, N.,Fujimoto, T.,Gomi, S.,Shiromizu, I.,Kawamoto, M.,Matsusue, T.,Shirouzu, M.,Yokoyama, S.
Inhibitor-bound structures of human pyruvate dehydrogenase kinase 4.
Acta Crystallogr.,Sect.D, 67:763-773, 2011

PubMed Abstract: The mitochondrial pyruvate dehydrogenase complex (PDC) catalyzes the oxidative decarboxylation of pyruvate to acetyl-CoA. PDC activity is tightly regulated by four members of a family of pyruvate dehydrogenase kinase isoforms (PDK1-4), which phosphorylate and inactivate PDC. Recently, the development of specific inhibitors of PDK4 has become an especially important focus for the pharmaceutical management of diabetes and obesity. In this study, crystal structures of human PDK4 complexed with either AMPPNP, ADP or the inhibitor M77976 were determined. ADP-bound PDK4 has a slightly wider active-site cleft and a more disordered ATP lid compared with AMPPNP-bound PDK4, although both forms of PDK4 assume open conformations with a wider active-site cleft than that in the closed conformation of the previously reported ADP-bound PDK2 structure. M77976 binds to the ATP-binding pocket of PDK4 and causes local conformational changes with complete disordering of the ATP lid. M77976 binding also leads to a large domain rearrangement that further expands the active-site cleft of PDK4 compared with the ADP- and AMPPNP-bound forms. Biochemical analyses revealed that M77976 inhibits PDK4 with increased potency compared with the previously characterized PDK inhibitor radicicol. Thus, the present structures demonstrate for the first time the flexible and dynamic aspects of PDK4 in the open conformation and provide a basis for the development of novel inhibitors targeting the nucleotide-binding pocket of PDK4.

PubMed: 21904029
DOI: 10.1107/S090744491102405X
主引用文献が同じPDBエントリー

実験手法

X-RAY DIFFRACTION (2.54 Å)