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X-ray structures of GluCl in apo states reveal a gating mechanism of Cys-loop receptors

机译：载脂蛋白状态的GluCl的X射线结构揭示了Cys环受体的门控机制

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摘要

根据其胚胎和离子选择性的不同，Cys-环受体是介导激发性或抑制性神经传输的、由神经传输物激活的离子通道。在这篇论文中，作者解决了 "谷氨酸盐门控的氯化物通道"（GluCI,它是来自线虫的一个Cys-环受体）在一个apo或闭合状态以及在一个与脂质相结合的状态下 的结构。将这些结构与以前发表的GluCI在一个与"伊维菌素"（ivermectin)相结合的状态下的结构所做比较，显示了当这种膜蛋白在闭合/静止状态和开启/激活状态之间转变时所发生的构形变化。%Cys-loop receptors are neurotransmitter-gated ion channels that are essential mediators of fast chemical neurotransmission and are associated with a large number of neurological diseases and disorders, as well as parasitic infections. Members of this ion channel superfamily mediate excitatory or inhibitory neurotransmission depending on their ligand and ion selectivity. Structural information for Cys-loop receptors comes from several sources including electron microscopic studies of the nicotinic acetylcholine receptor, high-resolution X-ray structures of extracellular domains and X-ray structures of bacterial orthologues. In 2011 our group published structures of the Caenorhabditis elegans glutamate-gated chloride channel (GluCl) in complex with the allosteric partial agonist ivermectin, which provided insights into the structure of a possibly open state of a eukaryotic Cys-loop receptor, the basis for anion selectivity and channel block, and the mechanism by which ivermectin and related molecules stabilize the open state and potentiate neurotransmitter binding . However, there remain unanswered questions about the mechanism of channel opening and closing, the location and nature of the shut ion channel gate, the transitions between the closed/ resting, open/activated and closed/desensitized states, and the mechanism by which conformational changes are coupled between the extracellular, orthosteric agonist binding domain and the transmembrane, ion channel domain. Here we present two conformationally distinct structures of C. elegans GluCl in the absence of ivermectin. Structural comparisons reveal a quaternary activation mechanism arising from rigid-body movements between the extracellular and transmembrane domains and a mechanism for modulation of the receptor by phospholipids.
机译：根据其胚胎和离子选择性的不同，Cys-环受体是介导激发性或抑制性神经传输的、由神经传输物激活的离子通道。在这篇论文中，作者解决了 "谷氨酸盐门控的氯化物通道"（GluCI,它是来自线虫的一个Cys-环受体）在一个apo或闭合状态以及在一个与脂质相结合的状态下 的结构。将这些结构与以前发表的GluCI在一个与"伊维菌素"（ivermectin)相结合的状态下的结构所做比较，显示了当这种膜蛋白在闭合/静止状态和开启/激活状态之间转变时所发生的构形变化。%Cys-loop receptors are neurotransmitter-gated ion channels that are essential mediators of fast chemical neurotransmission and are associated with a large number of neurological diseases and disorders, as well as parasitic infections. Members of this ion channel superfamily mediate excitatory or inhibitory neurotransmission depending on their ligand and ion selectivity. Structural information for Cys-loop receptors comes from several sources including electron microscopic studies of the nicotinic acetylcholine receptor, high-resolution X-ray structures of extracellular domains and X-ray structures of bacterial orthologues. In 2011 our group published structures of the Caenorhabditis elegans glutamate-gated chloride channel (GluCl) in complex with the allosteric partial agonist ivermectin, which provided insights into the structure of a possibly open state of a eukaryotic Cys-loop receptor, the basis for anion selectivity and channel block, and the mechanism by which ivermectin and related molecules stabilize the open state and potentiate neurotransmitter binding . However, there remain unanswered questions about the mechanism of channel opening and closing, the location and nature of the shut ion channel gate, the transitions between the closed/ resting, open/activated and closed/desensitized states, and the mechanism by which conformational changes are coupled between the extracellular, orthosteric agonist binding domain and the transmembrane, ion channel domain. Here we present two conformationally distinct structures of C. elegans GluCl in the absence of ivermectin. Structural comparisons reveal a quaternary activation mechanism arising from rigid-body movements between the extracellular and transmembrane domains and a mechanism for modulation of the receptor by phospholipids.

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  • 来源
    《Nature》 |2014年第7514期|333-337B2|共6页
  • 作者

    Thorsten Althoff; Ryan E. Hibbs; Surajit Banerjee; Eric Gouaux;

  • 作者单位

    Volium lnstitute,Oregon Health & Science University,3181 SW Sam Jackson Park Road, Portland,Oregon 97239, USA,Department of Physiology, David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, California 90095-1751, USA;

    Volium lnstitute,Oregon Health & Science University,3181 SW Sam Jackson Park Road, Portland,Oregon 97239, USA,Department of Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas 75390-9111, USA;

    NE-CAT/Corneli University,9700 South Cass Avenue, Building 436 E001,Argonne, Illinois 60439, USA;

    Volium lnstitute,Oregon Health & Science University,3181 SW Sam Jackson Park Road, Portland.Oregon 97239, USA,Howard Hughes Medical Institute, Oregon Health & 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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