Nicotinic acetylcholine receptors (nAChRs), belonging to the Cys-loop family of ligand-gated ion channels (LGICs), are integral membrane proteins comprising five identical or homologous subunits symmetrically arranged around a central pore. Each subunit consists of a large N-terminal extracellular domain (ECD), a transmembrane domain (TMD) comprising four membrane-spanning helices (M1-M4), and a variable cytoplasmic domain. Binding of endogenous ligand molecules - acetylcholine - to subunit interfaces in the ECD leads to the channel opening in the TMD, which is more than 40 Å away from the binding site. During the past few years, more than a dozen of high-resolution structures of the Cys-loop family receptors, including nicotinic acetylcholine, serotonin (5-HT3), g-aminobutyric acid (GABA) and glycine receptors, have become available, which were captured in a variety of functional states. However, recent molecular dynamics (MD) simulations have raised questions about the physiological relevance of several of these receptor structures, since the transmembrane pores rapidly collapse and become artificially asymmetric in the simulations. To address this issue, Damgen and Biggin developed an equilibration protocol that could avoid the collapse in the glycine receptor and lead to a stable open state. However, their protocol didn’t work for nAChRs or 5-HT3ARs, but utilizing their idea we have developed a set of new equilibration protocols that could produce stable open-channel structures for both nAChRs and 5-HT3ARs. Moreover, our equilibration protocols can also convert nAChR from a closed-channel structure to an open-channel structure, which may shed light on both common and divergent gating pathways in this family of receptors.

Conformational dynamics of the human α7 nicotinic acetylcholine receptor in three distinct functional states

ACS Spring 2022

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