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首页> 外文期刊>EMBO Journal >Crystal structure of pyruvate dehydrogenase kinase 3 bound to lipoyl domain 2 of human pyruvate dehydrogenase complex
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Crystal structure of pyruvate dehydrogenase kinase 3 bound to lipoyl domain 2 of human pyruvate dehydrogenase complex

机译：丙酮酸脱氢酶激酶的晶体结构3绑定lipoyl域2人丙酮酸脱氢酶复杂

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摘要

The human pyruvate dehydrogenase complex (PDC) is regulated by reversible phosphorylation by four isoforms of pyruvate dehydrogenase kinase (PDK). PDKs phosphorylate serine residues in the dehydrogenase (E1p) component of PDC, but their amino-acid sequences are unrelated to eukaryotic Ser/Thr/Tyr protein kinases. PDK3 binds to the inner lipoyl domains (L2) from the 60-meric transacetylase (E2p) core of PDC, with concomitant stimulated kinase activity. Here, we present crystal structures of the PDK3-L2 complex with and without bound ADP or ATP. These structures disclose that the C-terminal tail from one subunit of PDK3 dimer constitutes an integral part of the lipoyl-binding pocket in the N-terminal domain of the opposing subunit. The two swapped C-terminal tails promote conformational changes in active-site clefts of both PDK3 subunits, resulting in largely disordered ATP lids in the ADP-bound form. Our structural and biochemical data suggest that L2 binding stimulates PDK3 activity by disrupting the ATP lid, which otherwise traps ADP, to remove product inhibition exerted by this nucleotide. We hypothesize that this allosteric mechanism accounts, in part, for E2p-augmented PDK3 activity.
机译：人类的丙酮酸脱氢酶复合体(PDC)四个由可逆磷酸化丙酮酸脱氢酶激酶(此后)的亚型。此后使磷酸化丝氨酸残基PDC脱氢酶(E1p)的组成部分,但他们的氨基酸序列与真核无关对丝氨酸/苏氨酸/酪氨酸蛋白激酶。从60-meric内在lipoyl域(L2)转乙酰酶(E2p) PDC的核心同时刺激了激酶活性。现在PDK3-L2复杂的晶体结构和没有绑定ADP和ATP。披露,c端尾结构亚基之一PDK3二聚体构成一个积分lipoyl-binding口袋里的一部分反对亚基的n端结构域。两个交换c端反面宣传石穴构象变化的活性部位两PDK3子单元,从而在很大程度上无序的ATP盖子ADP-bound形式。结构和生化数据表明,L2绑定激发PDK3活动通过扰乱ATP盖子,否则陷阱ADP,删除由这个核苷酸产物抑制作用。假设这种变构机制账户,在某种程度上,对E2p-augmented PDK3活动。

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