title: Ligand-binding domain of an α7-nicotinic receptor chimera and its complex with agonist.
abstract: The α(7) acetylcholine receptor (AChR) mediates pre- and postsynaptic neurotransmission in the central nervous system and is a potential therapeutic target in neurodegenerative, neuropsychiatric and inflammatory disorders. We determined the crystal structure of the extracellular domain of a receptor chimera constructed from the human α(7) AChR and Lymnaea stagnalis acetylcholine binding protein (AChBP), which shares 64% sequence identity and 71% similarity with native α(7). We also determined the structure with bound epibatidine, a potent AChR agonist. Comparison of the structures revealed molecular rearrangements and interactions that mediate agonist recognition and early steps in signal transduction in α(7) AChRs. The structures further revealed a ring of negative charge within the central vestibule, poised to contribute to cation selectivity. Structure-guided mutational studies disclosed distinctive contributions to agonist recognition and signal transduction in α(7) AChRs. The structures provide a realistic template for structure-aided drug design and for defining structure-function relationships of α(7) AChRs.
authors: Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, California, USA.
authors: Shu-Xing
authors: SX
authors: Li
authors: Sun
authors: S
authors: Huang
authors: Nina
authors: N
authors: Bren
authors: Kaori
authors: K
authors: Noridomi
authors: Cosma D
authors: CD
authors: Dellisanti
authors: Steven M
authors: SM
authors: Sine
authors: Lin
authors: L
authors: Chen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002678:Chimera; D017124:Conserved Sequence / Q000187:drug effects / Q000235:genetics; D018360:Crystallography, X-Ray / Q000379:methods; D006801:Humans; D008024:Ligands; D008195:Lymnaea; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018722:Nicotinic Agonists / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011487:Protein Conformation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000187:drug effects
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D008024:Ligands; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C082748:epibatidine