6CNK

Structure of the 3alpha2beta stiochiometry of the human Alpha4Beta2 nicotinic receptor

Summary for 6CNK

• Entry DOI: 10.2210/pdb6cnk/pdb
• Related: 6CNJ
• EMDB information: 7535 7536
• Descriptor: Neuronal acetylcholine receptor subunit alpha-4, Neuronal acetylcholine receptor subunit beta-2, IgG1 Kappa Light Chain, ... (9 entities in total)
• Functional Keywords: ligand-gated ion channel, acetylcholine receptor, cys-loop receptor, membrane protein, transport protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 9
• Total formula weight: 390447.01

Authors

Walsh Jr, R.M.,Roh, S.H.,Gharpure, A.,Morales-Perez, C.L.,Hibbs, R.E. (deposition date: 2018-03-08, release date: 2018-05-02, Last modification date: 2020-07-29)

Primary citation

Walsh, R.M.,Roh, S.H.,Gharpure, A.,Morales-Perez, C.L.,Teng, J.,Hibbs, R.E.
Structural principles of distinct assemblies of the human alpha 4 beta 2 nicotinic receptor.
Nature, 557:261-265, 2018

PubMed Abstract: Fast chemical communication in the nervous system is mediated by neurotransmitter-gated ion channels. The prototypical member of this class of cell surface receptors is the cation-selective nicotinic acetylcholine receptor. As with most ligand-gated ion channels, nicotinic receptors assemble as oligomers of subunits, usually as hetero-oligomers and often with variable stoichiometries . This intrinsic heterogeneity in protein composition provides fine tunability in channel properties, which is essential to brain function, but frustrates structural and biophysical characterization. The α4β2 subtype of the nicotinic acetylcholine receptor is the most abundant isoform in the human brain and is the principal target in nicotine addiction. This pentameric ligand-gated ion channel assembles in two stoichiometries of α- and β-subunits (2α:3β and 3α:2β). Both assemblies are functional and have distinct biophysical properties, and an imbalance in the ratio of assemblies is linked to both nicotine addiction and congenital epilepsy. Here we leverage cryo-electron microscopy to obtain structures of both receptor assemblies from a single sample. Antibody fragments specific to β2 were used to 'break' symmetry during particle alignment and to obtain high-resolution reconstructions of receptors of both stoichiometries in complex with nicotine. The results reveal principles of subunit assembly and the structural basis of the distinctive biophysical and pharmacological properties of the two different stoichiometries of this receptor.

PubMed: 29720657
DOI: 10.1038/s41586-018-0081-7

Experimental method

ELECTRON MICROSCOPY (3.7 Å)