title: Design and Characterization of Superpotent Bivalent Ligands Targeting Oxytocin Receptor Dimers via a Channel-Like Structure.
abstract: Dimeric/oligomeric states of G-protein coupled receptors have been difficult to target. We report here bivalent ligands consisting of two identical oxytocin-mimetics that induce a three order magnitude boost in G-protein signaling of oxytocin receptors (OTRs) in vitro and a 100- and 40-fold gain in potency in vivo in the social behavior of mice and zebrafish. Through receptor mutagenesis and interference experiments with synthetic peptides mimicking transmembrane helices (TMH), we show that such superpotent behavior follows from the binding of the bivalent ligands to dimeric receptors based on a TMH1-TMH2 interface. Moreover, in this arrangement, only the analogues with a well-defined spacer length (∼25 Å) precisely fit inside a channel-like passage between the two protomers of the dimer. The newly discovered oxytocin bivalent ligands represent a powerful tool for targeting dimeric OTR in neurodevelopmental and psychiatric disorders and, in general, provide a framework to untangle specific arrangements of G-protein coupled receptor dimers.
authors.affiliation: CNR, Institute of Neuroscience , Milan, Italy 20129.|Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano , Milan, Italy 20129.
authors.forename: Marta
authors.initials: M
authors.lastname: Busnelli
authors.affiliation: Institute of Experimental Pediatric Endocrinology, Charité-Universitätsmedizin Berlin , Berlin, Germany 13353.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Kleinau
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland , Brisbane, Australia 4072.
authors.forename: Markus
authors.initials: M
authors.lastname: Muttenthaler
authors.affiliation: Department of Biochemistry and Cancer Biology, University of Toledo , Toledo, Ohio 43614, United States.
authors.forename: Stoytcho
authors.initials: S
authors.lastname: Stoev
authors.affiliation: Department of Biochemistry and Cancer Biology, University of Toledo , Toledo, Ohio 43614, United States.
authors.forename: Maurice
authors.initials: M
authors.lastname: Manning
authors.affiliation: School of Pharmacy, University of East Anglia , Norwich Research Park, Norwich, U.K. NR4 7TJ.
authors.forename: Lucka
authors.initials: L
authors.lastname: Bibic
authors.affiliation: School of Pharmacy, University of East Anglia , Norwich Research Park, Norwich, U.K. NR4 7TJ.
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Howell
authors.affiliation: School of Pharmacy, University of East Anglia , Norwich Research Park, Norwich, U.K. NR4 7TJ.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McCormick
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano , Milan, Italy 20129.
authors.forename: Simona
authors.initials: S
authors.lastname: Di Lascio
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano , Milan, Italy 20129.
authors.forename: Daniela
authors.initials: D
authors.lastname: Braida
authors.affiliation: CNR, Institute of Neuroscience , Milan, Italy 20129.|Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano , Milan, Italy 20129.
authors.forename: Mariaelvina
authors.initials: M
authors.lastname: Sala
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano , Milan, Italy 20133.
authors.forename: G Enrico
authors.initials: GE
authors.lastname: Rovati
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano , Milan, Italy 20129.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Bellini
authors.affiliation: CNR, Institute of Neuroscience , Milan, Italy 20129.
authors.forename: Bice
authors.initials: B
authors.lastname: Chini
mesh_terms: D000818:Animals; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D010121:Oxytocin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018045:Receptors, Oxytocin / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; C569600:OXTR protein, human; D018045:Receptors, Oxytocin; D010121:Oxytocin