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Crystal structure of an orthologue of the NaChBac voltage-gated sodium channel

机译：NaChBac电压门控钠通道直系同源物的晶体结构

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摘要

钾通道有很多已发表的结构，但关于“电压门rn控的钠”(Na_v)通道的结构信息却要少得多，rn尽管它们在神经细胞、肌肉细胞和心脏中的动rn作电位的启动和传播中有重要作用。细菌Narn通道为结构一功能分析提供了一个很好的模rn型系统，本期Nature上有两个小组报告了明显rn处于“非激活”构形的细菌Na通道的×-射线rn晶体结构。Nieng Yan及其同事以3.05埃的分rn辨率确定了来自名为“alplla proteobacterium rnHIMB114”的海洋细菌的Na.Rh的结构。William rnCatterall及其同事以33.2埃的分辨率报告了来自rnArcobacter butzleri、处于两个潜在“非激活”状rn态的Na.Ab)通道的晶体结构。将这些新获得的rn结构与以前所发表的、关于处在一种“pre-open”rn状态的Na.Ab的数据所做的对比，显示了可能rn决定这些通道的机电耦合机制的构形重排。rn这项工作对于各种“通道病”(channelopathies)、rn而且从更广泛意义上来说对于神经活性药物的rn设计都是具有相关性的。%Voltage-gated sodium (Na_v) channels are essential for the rapid depolarization of nerve and muscle, and are important drug targets. Determination of the structures of Na_v channels will shed light on ion channel mechanisms and facilitate potential clinical applications. A family of bacterial Na_v channels, exemplified by the Na~+-selective channel of bacteria (NaChBac), provides a useful model system for structure-function analysis. Here we report the crystal structure of Na,,Rh, a NaChBac orthologue from die marine alphaproteobac-terium HIMB114 (Rickettsiales sp. HIMB114; denoted Rh), at 3.05 A resolution. The channel comprises an asymmetric tetramer. The carbonyl oxygen atoms of Thr 178 and Leu 179 constitute an inner site within the selectivity filter where a hydrated Ca~(2+) resides in the crystal structure. The outer mouth of the Na~+ selectivity filter, defined by Ser 181 and Glu 183, is dosed, as is the activation gate at the intracellular side of the pore. The voltage sensors adopt a depolarized conformation in which all the gating charges are exposed to the extracellular environment. We propose that Na_v.Rh is in an 'inactivated' conformation. Comparison of Na_vRh with Na_vAb~4 reveals considerable conformational rearrangements that may underlie the electromechanical coupling mechanism of voltage-gated channels.
机译：钾通道有很多已发表的结构，但关于“电压门rn控的钠”(Na_v)通道的结构信息却要少得多，rn尽管它们在神经细胞、肌肉细胞和心脏中的动rn作电位的启动和传播中有重要作用。细菌Narn通道为结构一功能分析提供了一个很好的模rn型系统，本期Nature上有两个小组报告了明显rn处于“非激活”构形的细菌Na通道的×-射线rn晶体结构。Nieng Yan及其同事以3.05埃的分rn辨率确定了来自名为“alplla proteobacterium rnHIMB114”的海洋细菌的Na.Rh的结构。William rnCatterall及其同事以33.2埃的分辨率报告了来自rnArcobacter butzleri、处于两个潜在“非激活”状rn态的Na.Ab)通道的晶体结构。将这些新获得的rn结构与以前所发表的、关于处在一种“pre-open”rn状态的Na.Ab的数据所做的对比，显示了可能rn决定这些通道的机电耦合机制的构形重排。rn这项工作对于各种“通道病”(channelopathies)、rn而且从更广泛意义上来说对于神经活性药物的rn设计都是具有相关性的。%Voltage-gated sodium (Na_v) channels are essential for the rapid depolarization of nerve and muscle, and are important drug targets. Determination of the structures of Na_v channels will shed light on ion channel mechanisms and facilitate potential clinical applications. A family of bacterial Na_v channels, exemplified by the Na~+-selective channel of bacteria (NaChBac), provides a useful model system for structure-function analysis. Here we report the crystal structure of Na,,Rh, a NaChBac orthologue from die marine alphaproteobac-terium HIMB114 (Rickettsiales sp. HIMB114; denoted Rh), at 3.05 A resolution. The channel comprises an asymmetric tetramer. The carbonyl oxygen atoms of Thr 178 and Leu 179 constitute an inner site within the selectivity filter where a hydrated Ca~(2+) resides in the crystal structure. The outer mouth of the Na~+ selectivity filter, defined by Ser 181 and Glu 183, is dosed, as is the activation gate at the intracellular side of the pore. The voltage sensors adopt a depolarized conformation in which all the gating charges are exposed to the extracellular environment. We propose that Na_v.Rh is in an 'inactivated' conformation. Comparison of Na_vRh with Na_vAb~4 reveals considerable conformational rearrangements that may underlie the electromechanical coupling mechanism of voltage-gated channels.

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  • 来源
    《Nature》 |2012年第7401期|p.130-134A3|共6页
  • 作者

    Xu Zhang; Wenlin Ren; Paul DeCaen; Chuangye Yan; Xiao Tao; Lin Tang; Jingjing Wang; Kazuya Hasegawa; Takashi Kumasaka; Jianhua He; Jiawei Wang; David E. Clapham; Nieng Yan;

  • 作者单位

    State Key Laboratory of Bio-membrane and Membrane Biotechnology, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China. ,Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China;

    State Key Laboratory of Bio-membrane and Membrane Biotechnology, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China. ,Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China;

    Howard Hughes Medical Institute, Department of Cardiology, Children's Hospital Boston, Boston, Massachusetts 02115, USA,Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA;

    State Key Laboratory of Bio-membrane and Membrane Biotechnology, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China. ,Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China;

    Laboratory of Molecular Neurobiologyand Biophysics, Rockefeller University, Howard Hughes Medical Institute, 1230 York Avenue, New York, New York 10065, USA;

    Shanghai Institute of Applied Physics, Chinese Academy of Sciences, 239 Zhangheng Road, Shanghai 201204, China;

    State Key Laboratory of Drug Research, Shanghai Institute of MateriaMedica, Chinese Academy of Sciences, Shanghai 201203, China;

    Japan Synchrotron Radiation Research Institute (SPring-8), 1-1-1 Kouto, Sayo-cho, Sayo-gun, Hyogo 679-5198, Japan;

    Japan Synchrotron Radiation Research Institute (SPring-8), 1-1-1 Kouto, Sayo-cho, Sayo-gun, Hyogo 679-5198, Japan;

    Shanghai Institute of Applied Physics, Chinese Academy of Sciences, 239 Zhangheng Road, Shanghai 201204, China;

    State Key Laboratory of Bio-membrane and Membrane Biotechnology, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.;

    Howard Hughes Medical Institute, Department of Cardiology, Children's Hospital Boston, Boston, Massachusetts 02115, USA,Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA;

    State Key Laboratory of Bio-membrane and Membrane Biotechnology, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China. ,Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China;

  • 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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