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X - ray structures of LeuT in substrate -free outward-open and apo inward-open ststcs

机译：无底物向外开放和载脂蛋白向内开放的ststcs中LeuT的X射线结构

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摘要

Neurotransmitter sodium symporters are integral membrane proteins that remove chemical transmitters from the synapse and terminate neurotransmission mediated by serotonin, dopamine, noradrenaline, glycine and GAB A (γ-aminobutyric acid). Crystal structures of the bacterial homologue, LeuT, in substrate-bound outward-occluded and competitive inhibitor-bound outward-facing states have advanced our mechanistic understanding of neurotransmitter sodium symporters but have left fundamental questions unanswered. Here we report crystal structures of LeuT mutants in complexes with conformation-specific antibody fragments in the outward-open and inward-open states. In the absence of substrate but in the presence of sodium the transporter is outward-open, illustrating how the binding of substrate closes the extracellular gate through local conformational changes: hinge-bending movements of the extracellular halves of transmembrane domains 1, 2 and 6, together with translation of extracellular loop 4. The inward-open conformation, by contrast, involves large-scale conformational changes, including a reorientation of transmembrane domains 1, 2, 5, 6 and 7, a marked hinge bending of transmembrane domain la and occlusion of the extracellular vestibule by extracellular loop 4. These changes close the extracellular gate, open an intracellular vestibule, and largely disrupt the two sodium sites, thus providing a mechanism by which ions and substrate are released to the cytoplasm. The new structures establish a structural framework for the mechanism of neurotransmitter sodium symporters and their modulation by therapeutic and illicit substances.
机译：神经递质钠共转运蛋白是整合的膜蛋白，可从突触中去除化学递质，并终止由血清素，多巴胺，去甲肾上腺素，甘氨酸和GABA（γ-氨基丁酸）介导的神经传递。细菌同系物LeuT的晶体结构处于受底物结合的向外封闭和竞争性的抑制剂结合的朝外状态，这提高了我们对神经递质钠同向转运蛋白的机械理解，但未解决基本问题。在这里，我们报告了LeuT突变体的晶体结构，该结构在向外开放和向内开放状态下均具有构象特异性抗体片段。在没有底物但存在钠的情况下，转运蛋白向外开放，说明底物的结合如何通过局部构象变化关闭细胞外门：跨膜结构域1、2和6的细胞外半部的铰链弯曲运动。相反，胞外环4的翻译。向内开放构象涉及大规模构象变化，包括跨膜结构域1、2、5、6和7的重新定向，跨膜结构域1a的显着铰链弯曲和闭塞。这些变化通过细胞外环4引起细胞外前庭的关闭。这些变化关闭了细胞外门，打开了细胞内前庭，并在很大程度上破坏了两个钠位，从而提供了一种将离子和底物释放到细胞质的机制。新的结构为神经递质钠转运蛋白的机制及其通过治疗和非法物质的调节建立了结构框架。

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  • 来源
    《Nature》 |2012年第7382期|p.469-474|共6页
  • 作者

    Harini Krishnamurthy; Eric Gouaux;

  • 作者单位

    Vollum Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.;

    Vollum Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.,Howard Hughes Medical Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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