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

• DOI: 10.1101/2023.01.03.522595
• Publication Date: 2023-01-04T05:15:15Z
• Authors: Marie S. Prevost; Nathalie Barilone; Gabrielle Dejean ...; Stéphanie Pons; Gabriel Ayme; Patrick England; Marc Gielen; François Bontems; Gérard Pehau-Arna...; Uwe Maskos; Pierre Lafaye; Pierre-Jean Corri...
• Keywords: Allosteric modulator

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