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An allosteric binding site of the α7 nicotinic acetylcholine receptor revealed in a humanized acetylcholine binding protein

DOI: 10.1074/jbc.M117.815316 DOI Help

Authors: Florian Delbart (KU Leuven) , Marijke Brams (KU Leuven) , Fabian Gruss (KU Leuven) , Sam Noppen (KU Leuven) , Steve Peigneur (KU Leuven) , Sandro Boland (CISTIM) , Patrick Chaltin (CD3 KU Leuven) , Jose Brandao-Neto (Diamond Light Source) , Frank Von Delft (Diamond Light Source) , Wouter G. Touw (Netherlands Cancer Institute) , Robbie Joosten (Netherlands Cancer Institute) , Sandra Liekens (KU Leuven) , Jan Tytgat (KU Leuven) , Chris Ulens (KU Leuven)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Biological Chemistry

State: Published (Approved)
Published: December 2017

Open Access Open Access

Abstract: 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 & α7 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 α7-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 α7 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 β8-β9 loop, which critically contributes to coupling ligand binding to channel opening in human α7 nAChR. This work expands our understanding of the topology of allosteric binding sites in AChBP and, by extrapolation, in the human α7 nAChR as determined by electrophysiology measurements. Our insights pave the way for drug design strategies targeting nAChRs involved in ion channel-mediated disorders.

Journal Keywords: Cys-loop receptor; electrophysiology; neurotransmitter; nicotinic acetylcholine receptors (nAChR); X-ray crystallography; allosteric modulation; fragment-based screening; ligand-gated ion channel; structure-based drug discovery

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Other Facilities: SOLEIL

Added On: 14/12/2017 09:55


Discipline Tags:

Health & Wellbeing Neurology Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)