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Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors

Author

Listed:
  • KatjuS̆a Brejc

    (Netherlands Cancer Institute, Plesmanlaan 121)

  • Willem J. van Dijk

    (Netherlands Cancer Institute, Plesmanlaan 121)

  • Remco V. Klaassen

    (Research Institute Neurosciences Vrije Universiteit, Faculty of Biology, De Boelelaan 1087)

  • Mascha Schuurmans

    (Research Institute Neurosciences Vrije Universiteit, Faculty of Biology, De Boelelaan 1087)

  • John van der Oost

    (Research Institute Neurosciences Vrije Universiteit, Faculty of Biology, De Boelelaan 1087
    Wageningen University)

  • August B. Smit

    (Research Institute Neurosciences Vrije Universiteit, Faculty of Biology, De Boelelaan 1087)

  • Titia K. Sixma

    (Netherlands Cancer Institute, Plesmanlaan 121)

Abstract

Pentameric ligand gated ion-channels, or Cys-loop receptors, mediate rapid chemical transmission of signals. This superfamily of allosteric transmembrane proteins includes the nicotinic acetylcholine (nAChR), serotonin 5-HT3, γ-aminobutyric-acid (GABAA and GABAC) and glycine receptors. Biochemical and electrophysiological information on the prototypic nAChRs is abundant but structural data at atomic resolution have been missing. Here we present the crystal structure of molluscan acetylcholine-binding protein (AChBP), a structural and functional homologue of the amino-terminal ligand-binding domain of an nAChR α-subunit. In the AChBP homopentamer, the protomers have an immunoglobulin-like topology. Ligand-binding sites are located at each of five subunit interfaces and contain residues contributed by biochemically determined ‘loops’ A to F. The subunit interfaces are highly variable within the ion-channel family, whereas the conserved residues stabilize the protomer fold. This AChBP structure is relevant for the development of drugs against, for example, Alzheimer’s disease and nicotine addiction.

Suggested Citation

  • KatjuS̆a Brejc & Willem J. van Dijk & Remco V. Klaassen & Mascha Schuurmans & John van der Oost & August B. Smit & Titia K. Sixma, 2001. "Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors," Nature, Nature, vol. 411(6835), pages 269-276, May.
    • Handle: RePEc:nat:nature:v:411:y:2001:i:6835:d:10.1038_35077011
    DOI: 10.1038/35077011
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    Cited by:

    1. Dan Kozome & Adnan Sljoka & Paola Laurino, 2024. "Remote loop evolution reveals a complex biological function for chitinase enzymes beyond the active site," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    2. Shaotong Zhu & Akshay Sridhar & Jinfeng Teng & Rebecca J. Howard & Erik Lindahl & Ryan E. Hibbs, 2022. "Structural and dynamic mechanisms of GABAA receptor modulators with opposing activities," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    3. Deena R Schmidt & Roberto F Galán & Peter J Thomas, 2018. "Stochastic shielding and edge importance for Markov chains with timescale separation," PLOS Computational Biology, Public Library of Science, vol. 14(6), pages 1-35, June.

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