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Nature 411, 269-276 (17 May 2001) | doi:10.1038/35077011; Received 4 January 2001; Accepted 21 March 2001

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

KatjuS brevea Brejc1, Willem J. van Dijk1, Remco V. Klaassen2, Mascha Schuurmans2, John van der Oost2,3, August B. Smit2 & Titia K. Sixma1

  1. Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
  2. Department of Molecular and Cellular Neurobiology, Research Institute Neurosciences Vrije Universiteit, Faculty of Biology, De Boelelaan 1087, 1081 HV Amsterdam, The Netherlands
  3. Present address: Laboratory of Microbiology, Department of Agrotechnology and Food Sciences, Wageningen University, Hesselink van Suchtelenweg 4, 6703 CT Wageningen, The Netherlands.

Correspondence to: Titia K. Sixma1 Correspondence should be addressed to T.K.S. (e-mail: Email: sixma@nki.nl). The structure has been deposited in the PDB with ID number 1I9B.

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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, italic gamma-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 alpha-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.

  1. Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
  2. Department of Molecular and Cellular Neurobiology, Research Institute Neurosciences Vrije Universiteit, Faculty of Biology, De Boelelaan 1087, 1081 HV Amsterdam, The Netherlands
  3. Present address: Laboratory of Microbiology, Department of Agrotechnology and Food Sciences, Wageningen University, Hesselink van Suchtelenweg 4, 6703 CT Wageningen, The Netherlands.

Correspondence to: Titia K. Sixma1 Correspondence should be addressed to T.K.S. (e-mail: Email: sixma@nki.nl). The structure has been deposited in the PDB with ID number 1I9B.