"INSIGHTS INTO LIGAND RECOGNITION AND DESENSITIZATION FROM THE X-RAY STRUCTURE OF A NICOTINIC RECEPTOR"
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.
Date: 31 March 2017, 14:15 (Friday, 11th week, Hilary 2017)
Venue: Wellcome Trust Centre for Human Genetics, Headington OX3 7BN
Venue Details: Meeting Room A
Speaker: Asst. Prof Ryan Hibbs (UT Southwestern Medical Center)
Organising department: Wellcome Trust Centre for Human Genetics
Organiser: Agata Krupa (Wellcome Trust Centre for Human Genetics)
Organiser contact email address: grunewald-pa@strubi.ox.ac.uk
Host: Prof Radu Aricescu ((Division of Structural Biology) University of Oxford)
Part of: Strubi seminars
Booking required?: Not required
Audience: Members of the University only
Editor: Agata Krupa