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Cryo-EM structure of 5-HT3A receptor in its resting conformation

Author

Listed:
  • Sandip Basak

    (Case Western Reserve University)

  • Yvonne Gicheru

    (Case Western Reserve University)

  • Amrita Samanta

    (Case Western Reserve University)

  • Sudheer Kumar Molugu

    (Case Western Reserve University)

  • Wei Huang

    (Case Western Reserve University)

  • Maria la de Fuente

    (Case Western Reserve University)

  • Taylor Hughes

    (Case Western Reserve University)

  • Derek J. Taylor

    (Case Western Reserve University)

  • Marvin T. Nieman

    (Case Western Reserve University)

  • Vera Moiseenkova-Bell

    (Case Western Reserve University
    Case Western Reserve University)

  • Sudha Chakrapani

    (Case Western Reserve University
    Case Western Reserve University)

Abstract

Serotonin receptors (5-HT3AR) directly regulate gut movement, and drugs that inhibit 5-HT3AR function are used to control emetic reflexes associated with gastrointestinal pathologies and cancer therapies. The 5-HT3AR function involves a finely tuned orchestration of three domain movements that include the ligand-binding domain, the pore domain, and the intracellular domain. Here, we present the structure from the full-length 5-HT3AR channel in the apo-state determined by single-particle cryo-electron microscopy at a nominal resolution of 4.3 Å. In this conformation, the ligand-binding domain adopts a conformation reminiscent of the unliganded state with the pore domain captured in a closed conformation. In comparison to the 5-HT3AR crystal structure, the full-length channel in the apo-conformation adopts a more expanded conformation of all the three domains with a characteristic twist that is implicated in gating.

Suggested Citation

  • Sandip Basak & Yvonne Gicheru & Amrita Samanta & Sudheer Kumar Molugu & Wei Huang & Maria la de Fuente & Taylor Hughes & Derek J. Taylor & Marvin T. Nieman & Vera Moiseenkova-Bell & Sudha Chakrapani, 2018. "Cryo-EM structure of 5-HT3A receptor in its resting conformation," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-02997-4
    DOI: 10.1038/s41467-018-02997-4
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    Cited by:

    1. Arvind Kumar & Kayla Kindig & Shanlin Rao & Afroditi-Maria Zaki & Sandip Basak & Mark S. P. Sansom & Philip C. Biggin & Sudha Chakrapani, 2022. "Structural basis for cannabinoid-induced potentiation of alpha1-glycine receptors in lipid nanodiscs," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Maegan M Weltzin & Andrew A George & Ronald J Lukas & Paul Whiteaker, 2021. "Sleep-related hypermotor epilepsy associated mutations uncover important kinetic roles of α4β2- nicotinic acetylcholine receptor intracellular structures," PLOS ONE, Public Library of Science, vol. 16(3), pages 1-38, March.
    3. Nikhil Bharambe & Zhuowen Li & David Seiferth & Asha Manikkoth Balakrishna & Philip C. Biggin & Sandip Basak, 2024. "Cryo-EM structures of prokaryotic ligand-gated ion channel GLIC provide insights into gating in a lipid environment," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    4. Vasyl Bondarenko & Marta M. Wells & Qiang Chen & Tommy S. Tillman & Kevin Singewald & Matthew J. Lawless & Joel Caporoso & Nicole Brandon & Jonathan A. Coleman & Sunil Saxena & Erik Lindahl & Yan Xu &, 2022. "Structures of highly flexible intracellular domain of human α7 nicotinic acetylcholine receptor," Nature Communications, Nature, vol. 13(1), pages 1-9, December.

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