A nanobody activating metabotropic glutamate receptor 4 discriminates between homo- and heterodimers

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 33; p. 1
• Main Authors: Haubrich, Jordi, Font, Joan, Quast, Robert B, Goupil-Lamy, Anne, Scholler, Pauline, Nevoltris, Damien, Acher, Francine, Chames, Patrick, Rondard, Philippe, Prézeau, Laurent, Pin, Jean-Philippe
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 17.08.2021
• Subjects: Allosteric properties; Antibodies; Biological Sciences; Cellular Biology; Gene Expression Regulation - drug effects; Glutamic acid receptors; Glutamic acid receptors (metabotropic); Humans; Life Sciences; Models, Biological; Molecular modelling; Mutagenesis; Mutation; Nanobodies; Protein Binding; Protein Conformation; Receptors; Receptors, Metabotropic Glutamate - agonists; Receptors, Metabotropic Glutamate - genetics; Receptors, Metabotropic Glutamate - metabolism; Selectivity; Single-Domain Antibodies; Synapses; G protein–coupled receptor; agonist; single-domain antibody; activation mechanism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2105848118

There is growing interest in developing biologics due to their high target selectivity. The G protein-coupled homo- and heterodimeric metabotropic glutamate (mGlu) receptors regulate many synapses and are promising targets for the treatment of numerous brain diseases. Although subtype-selective allosteric small molecules have been reported, their effects on the recently discovered heterodimeric receptors are often not known. Here, we describe a nanobody that specifically and fully activates homodimeric human mGlu4 receptors. Molecular modeling and mutagenesis studies revealed that the nanobody acts by stabilizing the closed active state of the glutamate binding domain by interacting with both lobes. In contrast, this nanobody does not activate the heterodimeric mGlu2-4 but acts as a pure positive allosteric modulator. These data further reveal how an antibody can fully activate a class C receptor and bring further evidence that nanobodies represent an alternative way to specifically control mGlu receptor subtypes.