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

KatjuS̆a Brejc, Willem J. van Dijk, Remco V. Klaassen, Mascha Schuurmans, John van der Oost, August B. Smit and Titia K. Sixma ()
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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
August B. Smit: Research Institute Neurosciences Vrije Universiteit, Faculty of Biology, De Boelelaan 1087
Titia K. Sixma: Netherlands Cancer Institute, Plesmanlaan 121

Nature, 2001, vol. 411, issue 6835, 269-276

Abstract: 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.

Date: 2001
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DOI: 10.1038/35077011

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