Ligand-binding domain of an ?7-nicotinic receptor chimera and its complex with agonist.
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ABSTRACT: The ?(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 ?(7) AChR and Lymnaea stagnalis acetylcholine binding protein (AChBP), which shares 64% sequence identity and 71% similarity with native ?(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 ?(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 ?(7) AChRs. The structures provide a realistic template for structure-aided drug design and for defining structure-function relationships of ?(7) AChRs.
SUBMITTER: Li SX
PROVIDER: S-EPMC3489043 | biostudies-literature | 2011 Sep
REPOSITORIES: biostudies-literature
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