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Publication Abstract from PubMed

Nicotinic acetylcholine receptors (nAChRs) belong to the family of pentameric ligand-gated ion channels and mediate fast excitatory transmission in the central and peripheral nervous systems. Among the different existing receptor subtypes, the homomeric & alpha7 nAChR has attracted considerable attention because of its possible implication in several neurological and psychiatric disorders, including cognitive decline associated with Alzheimer's disease or schizophrenia. Allosteric modulators of ligand-gated ion channels are of particular interest as therapeutic agents, as they modulate receptor activity without affecting normal fluctuations of synaptic neurotransmitter release. Here, we used X-ray crystallography and surface plasmon resonance spectroscopy of alpha7-acetylcholine binding protein (AChBP), a humanized chimera of a snail AChBP, which has 71% sequence similarity with the extracellular ligand-binding domain of the human alpha7 nAChR, to investigate the structural determinants of allosteric modulation. We extended previous observations that an allosteric site located in the vestibule of the receptor offers an attractive target for receptor modulation. We introduced seven additional humanizing mutations in the vestibule-located binding site of AChBP to improve its suitability as a model for studying allosteric binding. Using a fragment-based screening approach, we uncovered an allosteric binding site located near the beta8-beta9 loop, which critically contributes to coupling ligand binding to channel opening in human alpha7 nAChR. This work expands our understanding of the topology of allosteric binding sites in AChBP and, by extrapolation, in the human alpha7 nAChR as determined by electrophysiology measurements. Our insights pave the way for drug design strategies targeting nAChRs involved in ion channel-mediated disorders.

An allosteric binding site of the alpha7 nicotinic acetylcholine receptor revealed in a humanized acetylcholine binding protein.,Delbart F, Brams M, Gruss F, Noppen S, Peigneur S, Boland S, Chaltin P, Brandao-Neto J, von Delft F, Touw WG, Joosten R, Liekens S, Tytgat J, Ulens C J Biol Chem. 2017 Dec 13. pii: M117.815316. doi: 10.1074/jbc.M117.815316. PMID:29237730^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.