Centre National de la Recherche Scientifique (CNRS)
France
iNEXT-Discovery
European Union
Agence Nationale de la Recherche (ANR)
ANR-21-CE37-0026
France
Citation
Journal: Nat Commun / Year: 2023 Title: An original potentiating mechanism revealed by the cryo-EM structures of the human α7 nicotinic receptor in complex with nanobodies. Authors: 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 ...Authors: 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 / Pierre-Jean Corringer / 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 ...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.
Entire : Complex of the human alpha7 nicotinic acetylcholine receptor with...
Entire
Name: Complex of the human alpha7 nicotinic acetylcholine receptor with the Nanobody C4 and with Nicotine
Components
Complex: Complex of the human alpha7 nicotinic acetylcholine receptor with the Nanobody C4 and with Nicotine
Complex: human alpha7 nicotinic acetylcholine receptor
Protein or peptide: Neuronal acetylcholine receptor subunit alpha-7
Complex: Nanobody C4
Protein or peptide: Nanobody C4
Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
-
Supramolecule #1: Complex of the human alpha7 nicotinic acetylcholine receptor with...
Supramolecule
Name: Complex of the human alpha7 nicotinic acetylcholine receptor with the Nanobody C4 and with Nicotine type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)
Organism: Homo sapiens (human)
Molecular weight
Theoretical: 250 KDa
-
Supramolecule #2: human alpha7 nicotinic acetylcholine receptor
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