Insights into ligand recognition and desensitization from the x-ray structure of a nicotinic receptor

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• Ryan Hibbs, UT Southwestern
• Thursday 30 March 2017, 10:00-11:00
• MRC LMB: Max Perutz Lecture Theatre.

If you have a question about this talk, please contact Robert Jones.

Nicotinic acetylcholine receptors are ligand gated ion channels that mediate fast chemical neurotransmission at the neuromuscular junction and play diverse signaling roles in the central nervous system. The vast majority of these and other pentameric receptors in the superfamily assemble as obligate heteromers. Here I will present methods we developed for expression and biochemical characterization of heteromeric ion channels and present the first X-ray crystal structure of a nicotinic receptor. The alpha4beta2 nicotinic receptor that we characterized structurally is the most abundant receptor subtype in the brain, is the principal target in nicotine addiction and its dysfunction is associated with familial epilepsy. The structure of the receptor in complex with the agonist nicotine reveals principles of ligand selectivity among different classes of subunit interfaces in the heteropentameric assembly. The receptor is stabilized by nicotine in what we suggest is a non-conducting, desensitized conformation. The constriction point in the permeation pathway is formed at the selectivity filter, located at the cytosolic end of the pore. The desensitized state of this channel provides a distinct structural reference point in the allosteric gating cycle of the larger Cys-loop receptor superfamily.

This talk is part of the MRC LMB Neurobiology Seminars series.

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