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首页> 外文期刊>Acta crystallographica.Section D. Biological crystallography >Inhibitor-bound structures of human pyruvate dehydrogenase kinase 4.
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Inhibitor-bound structures of human pyruvate dehydrogenase kinase 4.

机译：Inhibitor-bound人类丙酮酸的结构脱氢酶激酶4。

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摘要

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.
机译：线粒体丙酮酸脱氢酶复合体(PDC)催化氧化脱酸丙酮酸乙酰辅酶a。丙酮酸的由四个家庭成员脱氢酶激酶(PDK1-4)使磷酸化和灭活PDC。PDK4特定抑制剂的发展成为一个尤其重要的焦点糖尿病和药品管理肥胖。人类PDK4 AMPPNP包裹着,ADP或抑制剂M77976下定了决心。PDK4略有更广泛的活性部位间隙和与相比更无序ATP盖子AMPPNP-bound PDK4,尽管这两种PDK4形式认为开放与更广泛的构象活性部位间隙比关闭之前报道的构象ADP-boundPDK2结构。口袋PDK4,导致当地的构象变化完全无序化的ATP盖子。M77976绑定也会导致一个大领域重排,进一步扩展了活性部位的裂缝PDK4与ADP -和AMPPNP-bound形式。透露,M77976抑制PDK4与增加力量与以前相比此后抑制剂radicicol特点。目前结构首次展示PDK4的灵活和动态方面开放构型,并提供一个基础新型抑制剂的发展目标nucleotide-binding PDK4的口袋里。

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