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

• Published in: Nature (London) Vol. 411; no. 6835; pp. 269 - 276
• Main Authors: Sixma, Titia K, Brejc, Katju a, van Dijk, Willem J, Klaassen, Remco V, Schuurmans, Mascha, van der Oost, John, Smit, August B
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 17-05-2001; Nature Publishing Group
• Subjects: Acetylcholine - metabolism; Acetylcholine-binding protein; Alzheimer's disease; Amino Acid Sequence; Animals; Binding Sites; Biochemistry; Biological and medical sciences; Carrier Proteins - chemistry; Carrier Proteins - metabolism; Crystal structure; Crystalline structure; Crystallography; Crystallography, X-Ray; Dimerization; Fundamental and applied biological sciences. Psychology; Immunoglobulins - chemistry; Ion Channel Gating; Ion Channels - chemistry; Ion Channels - metabolism; Ions; Laboratorium voor Microbiologie; Ligands; Lymnaea - chemistry; Microbiological Laboratory; Microbiologie; Microbiology; Models, Molecular; Molecular biophysics; Molecular Sequence Data; Mollusca; Mollusks; Neurons; Nicotine; Pichia; Protein Structure, Quaternary; Protein Structure, Tertiary; Protein Subunits; Proteins; Receptors; Receptors, Nicotinic - chemistry; Receptors, Nicotinic - metabolism; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Residues; Sequence Alignment; Serotonin; Structure in molecular biology; Topology; VLAG; Lymnaea stagnalis; Binding protein; Pulmonata; Three dimensional structure; Ligand; Acetylcholine; Binding site; Gastropoda; Invertebrata; Mollusca; Nicotinic receptor; Crystalline structure
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/35077011

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, 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.