9QTN

Human alpha7 nicotinic receptor in complex with the F1 nanobody

Summary for 9QTN

• Entry DOI: 10.2210/pdb9qtn/pdb
• EMDB information: 53355
• Descriptor: Neuronal acetylcholine receptor subunit alpha-7, Nanobody F1, alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• Functional Keywords: nicotinic receptor, nanobody, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 10
• Total formula weight: 353382.04

Authors

Barilone, N.,Vangelatou, M.,Marouf, F.Z.,Dejean de la Batie, G.,Ayme, G.,Lafaye, P.,Corringer, P.-J.,Prevost, M.S. (deposition date: 2025-04-09, release date: 2026-02-18)

Primary citation

Barilone, N.,Vangelatou, M.,Marouf, F.Z.,Dejean de la Batie, G.,Li, Q.,Lafaye, P.,Ayme, G.,Corringer, P.J.,Prevost, M.S.
Discovery and mechanism of negative allosteric modulation of the alpha 7 nicotinic acetylcholine receptor by nanobodies.
Proc.Natl.Acad.Sci.USA, 123:e2514734123-e2514734123, 2026

PubMed Abstract: α7 nicotinic receptors are neurotransmitter-gated ion channels involved in neurological and inflammatory diseases. Ligands acting on its neurotransmitter binding site and on the channel domain of α7 have been extensively developed, yielding a wide range of orthosteric effectors and allosteric positive modulators. Here, we present the functional and structural characterization of two camelid antibody fragments, or nanobodies, F1 and E6, that inhibit α7 activity by acting as negative allosteric modulators, an underrepresented class of ligands. Cryo-EM structures of the nanobodies in complex with α7 show that both nanobodies form a pentameric bundle at the apex of the receptor, each nanobody interacting through a conserved set of residues at α7 subunit interfaces. Electrophysiological experiments suggest that E6 inhibits the activity of α7 by stabilizing its resting conformation, and that internanobodies interactions are key to its activity. Those two nanobodies expand the toolbox for human α7 modulation, opening new possibilities for its pharmacological control with far reaching potentialities in clinics.

PubMed: 41576092
DOI: 10.1073/pnas.2514734123

Experimental method

ELECTRON MICROSCOPY (2.28 Å)