An original potentiating mechanism revealed by the cryo-EM structures of the human α7 nicotinic receptor in complex with nanobodies

Marie S. Prevost (), Nathalie Barilone, Gabrielle Dejean de la Bâtie, Stéphanie Pons, Gabriel Ayme, Patrick England, Marc Gielen, François Bontems, Gérard Pehau-Arnaudet, Uwe Maskos, Pierre Lafaye and Pierre-Jean Corringer ()
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Marie S. Prevost: Institut Pasteur, Université Paris Cité, CNRS UMR 3571, Channel-Receptors Unit
Nathalie Barilone: Institut Pasteur, Université Paris Cité, CNRS UMR 3571, Channel-Receptors Unit
Gabrielle Dejean de la Bâtie: Institut Pasteur, Université Paris Cité, CNRS UMR 3571, Channel-Receptors Unit
Stéphanie Pons: Institut Pasteur, Université Paris Cité, CNRS UMR 3571, Integrative Neurobiology of Cholinergic Systems Unit
Gabriel Ayme: Institut Pasteur, Université Paris Cité, CNRS UMR 3528, Antibody Engineering Platform
Patrick England: Institut Pasteur, Université Paris Cité, CNRS UMR 3528, Molecular Biophysics Platform
Marc Gielen: Institut Pasteur, Université Paris Cité, CNRS UMR 3571, Channel-Receptors Unit
François Bontems: Institut Pasteur, Université Paris Cité, CNRS UMR 3569, Structural Virology Unit
Gérard Pehau-Arnaudet: Institut Pasteur, Université Paris Cité, Ultrastructural Bioimaging Core Facility
Uwe Maskos: Institut Pasteur, Université Paris Cité, CNRS UMR 3571, Integrative Neurobiology of Cholinergic Systems Unit
Pierre Lafaye: Institut Pasteur, Université Paris Cité, CNRS UMR 3528, Antibody Engineering Platform
Pierre-Jean Corringer: Institut Pasteur, Université Paris Cité, CNRS UMR 3571, Channel-Receptors Unit

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract The human α7 nicotinic receptor is a pentameric channel mediating cellular and neuronal communication. It has attracted considerable interest in designing ligands for the treatment of neurological and psychiatric disorders. To develop a novel class of α7 ligands, we recently generated two nanobodies named E3 and C4, acting as positive allosteric modulator and silent allosteric ligand, respectively. Here, we solved the cryo-electron microscopy structures of the nanobody-receptor complexes. E3 and C4 bind to a common epitope involving two subunits at the apex of the receptor. They form by themselves a symmetric pentameric assembly that extends the extracellular domain. Unlike C4, the binding of E3 drives an agonist-bound conformation of the extracellular domain in the absence of an orthosteric agonist, and mutational analysis shows a key contribution of an N-linked sugar moiety in mediating E3 potentiation. The nanobody E3, by remotely controlling the global allosteric conformation of the receptor, implements an original mechanism of regulation that opens new avenues for drug design.

Date: 2023
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DOI: 10.1038/s41467-023-41734-4

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