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Structural mechanism of C-type inactivation in K+ channels

Author

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  • Luis G. Cuello

    (and Institute for Biophysical Dynamics, University of Chicago
    Present addresses: Department of Cell Physiology and Molecular Biophysics, Texas Tech University, Lubbock, Texas 79430, USA (L.G.C., D.M.C.); D. E. Shaw Research, Hyderabad 500034, India (V.J.).)

  • Vishwanath Jogini

    (and Institute for Biophysical Dynamics, University of Chicago
    Present addresses: Department of Cell Physiology and Molecular Biophysics, Texas Tech University, Lubbock, Texas 79430, USA (L.G.C., D.M.C.); D. E. Shaw Research, Hyderabad 500034, India (V.J.).)

  • D. Marien Cortes

    (and Institute for Biophysical Dynamics, University of Chicago
    Present addresses: Department of Cell Physiology and Molecular Biophysics, Texas Tech University, Lubbock, Texas 79430, USA (L.G.C., D.M.C.); D. E. Shaw Research, Hyderabad 500034, India (V.J.).)

  • Eduardo Perozo

    (and Institute for Biophysical Dynamics, University of Chicago)

Abstract

Interconversion between conductive and non-conductive forms of the K+ channel selectivity filter underlies a variety of gating events, from flicker transitions (at the microsecond timescale) to C-type inactivation (millisecond to second timescale). Here we report the crystal structure of the Streptomyces lividans K+ channel KcsA in its open-inactivated conformation and investigate the mechanism of C-type inactivation gating at the selectivity filter from channels ‘trapped’ in a series of partially open conformations. Five conformer classes were identified with openings ranging from 12 Å in closed KcsA (Cα–Cα distances at Thr 112) to 32 Å when fully open. They revealed a remarkable correlation between the degree of gate opening and the conformation and ion occupancy of the selectivity filter. We show that a gradual filter backbone reorientation leads first to a loss of the S2 ion binding site and a subsequent loss of the S3 binding site, presumably abrogating ion conduction. These structures indicate a molecular basis for C-type inactivation in K+ channels.

Suggested Citation

  • Luis G. Cuello & Vishwanath Jogini & D. Marien Cortes & Eduardo Perozo, 2010. "Structural mechanism of C-type inactivation in K+ channels," Nature, Nature, vol. 466(7303), pages 203-208, July.
    • Handle: RePEc:nat:nature:v:466:y:2010:i:7303:d:10.1038_nature09153
    DOI: 10.1038/nature09153
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    Citations

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    Cited by:

    1. Jeroen I Stas & Elke Bocksteins & Alain J Labro & Dirk J Snyders, 2015. "Modulation of Closed−State Inactivation in Kv2.1/Kv6.4 Heterotetramers as Mechanism for 4−AP Induced Potentiation," PLOS ONE, Public Library of Science, vol. 10(10), pages 1-21, October.
    2. Huiwen Chen & Zhanyi Xia & Jie Dong & Bo Huang & Jiangtao Zhang & Feng Zhou & Rui Yan & Yiqiang Shi & Jianke Gong & Juquan Jiang & Zhuo Huang & Daohua Jiang, 2024. "Structural mechanism of voltage-gated sodium channel slow inactivation," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    3. Cheng Zhao & Yuan Xie & Lizhen Xu & Fan Ye & Ximing Xu & Wei Yang & Fan Yang & Jiangtao Guo, 2022. "Structures of a mammalian TRPM8 in closed state," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    4. Mingfeng Zhang & Yuanyue Shan & Duanqing Pei, 2023. "Mechanism underlying delayed rectifying in human voltage-mediated activation Eag2 channel," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    5. Purushotham Selvakumar & Ana I. Fernández-Mariño & Nandish Khanra & Changhao He & Alice J. Paquette & Bing Wang & Ruiqi Huang & Vaughn V. Smider & William J. Rice & Kenton J. Swartz & Joel R. Meyerson, 2022. "Structures of the T cell potassium channel Kv1.3 with immunoglobulin modulators," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    6. Carus H. Y. Lau & Emelie Flood & Mark J. Hunter & Billy J. Williams-Noonan & Karen M. Corbett & Chai-Ann Ng & James C. Bouwer & Alastair G. Stewart & Eduardo Perozo & Toby W. Allen & Jamie I. Vandenbe, 2024. "Potassium dependent structural changes in the selectivity filter of HERG potassium channels," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    7. Adam Lewis & Vilius Kurauskas & Marco Tonelli & Katherine Henzler-Wildman, 2021. "Ion-dependent structure, dynamics, and allosteric coupling in a non-selective cation channel," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    8. Ahmed Rohaim & Bram J. A. Vermeulen & Jing Li & Felix Kümmerer & Federico Napoli & Lydia Blachowicz & João Medeiros-Silva & Benoît Roux & Markus Weingarth, 2022. "A distinct mechanism of C-type inactivation in the Kv-like KcsA mutant E71V," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    9. Yue Wang & Yixiao Hu & Jian-Ping Guo & Jun Gao & Bo Song & Lei Jiang, 2024. "A physical derivation of high-flux ion transport in biological channel via quantum ion coherence," Nature Communications, Nature, vol. 15(1), pages 1-8, December.

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