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Structure of the pentameric ligand-gated ion channel ELIC cocrystallized with its competitive antagonist acetylcholine

Author

Listed:
  • Jianjun Pan

    (2057 Biomedical Science Tower 3, 3501 Fifth Avenue, University of Pittsburgh School of Medicine)

  • Qiang Chen

    (2057 Biomedical Science Tower 3, 3501 Fifth Avenue, University of Pittsburgh School of Medicine)

  • Dan Willenbring

    (2057 Biomedical Science Tower 3, 3501 Fifth Avenue, University of Pittsburgh School of Medicine)

  • Ken Yoshida

    (2057 Biomedical Science Tower 3, 3501 Fifth Avenue, University of Pittsburgh School of Medicine)

  • Tommy Tillman

    (2057 Biomedical Science Tower 3, 3501 Fifth Avenue, University of Pittsburgh School of Medicine)

  • Ossama B. Kashlan

    (S931 Scaife, 3550 Terrace St, University of Pittsburgh School of Medicine)

  • Aina Cohen

    (Stanford Synchrotron Radiation Lightsource)

  • Xiang-Peng Kong

    (550 First Avenue, MSB 329, New York University School of Medicine)

  • Yan Xu

    (2057 Biomedical Science Tower 3, 3501 Fifth Avenue, University of Pittsburgh School of Medicine
    2048 Biomedical Science Tower 3, 3501 Fifth Avenue, University of Pittsburgh School of Medicine
    2048 Biomedical Science Tower 3, 3501 Fifth Avenue, University of Pittsburgh School of Medicine)

  • Pei Tang

    (2057 Biomedical Science Tower 3, 3501 Fifth Avenue, University of Pittsburgh School of Medicine
    2049 Biomedical Science Tower 3, 3501 Fifth Avenue, University of Pittsburgh School of Medicine
    2049 Biomedical Science Tower 3, 3501 Fifth Avenue, University of Pittsburgh School of Medicine)

Abstract

ELIC, the pentameric ligand-gated ion channel from Erwinia chrysanthemi, is a prototype for Cys-loop receptors. Here we show that acetylcholine is a competitive antagonist for ELIC. We determine the acetylcholine–ELIC cocrystal structure to a 2.9-Å resolution and find that acetylcholine binding to an aromatic cage at the subunit interface induces a significant contraction of loop C and other structural rearrangements in the extracellular domain. The side chain of the pore-lining residue F247 reorients and the pore size consequently enlarges, but the channel remains closed. We attribute the inability of acetylcholine to activate ELIC primarily to weak cation-π and electrostatic interactions in the pocket, because an acetylcholine derivative with a simple quaternary-to-tertiary ammonium substitution activates the channel. This study presents a compelling case for understanding the structural underpinning of the functional relationship between agonism and competitive antagonism in the Cys-loop receptors, providing a new framework for developing novel therapeutic drugs.

Suggested Citation

  • Jianjun Pan & Qiang Chen & Dan Willenbring & Ken Yoshida & Tommy Tillman & Ossama B. Kashlan & Aina Cohen & Xiang-Peng Kong & Yan Xu & Pei Tang, 2012. "Structure of the pentameric ligand-gated ion channel ELIC cocrystallized with its competitive antagonist acetylcholine," Nature Communications, Nature, vol. 3(1), pages 1-8, January.
    • Handle: RePEc:nat:natcom:v:3:y:2012:i:1:d:10.1038_ncomms1703
    DOI: 10.1038/ncomms1703
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    Cited by:

    1. 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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