Design and characterization of superpotent bivalent ligands targeting oxytocin receptor dimers via a channel-like structure

Busnelli, Marta, Kleinau, Gunnar, Muttenthaler, Markus, Stoev, Stoytcho, Manning, Maurice, Bibic, Lucka, Howell, Lesley A., McCormick, Peter J., Di Lascio, Simona, Braida, Daniela, Sala, Mariaelvina, Rovati, G. Enrico, Bellini, Tommaso and Chini, Bice (2016) Design and characterization of superpotent bivalent ligands targeting oxytocin receptor dimers via a channel-like structure. Journal of Medicinal Chemistry, 59 15: 7152-7166. doi:10.1021/acs.jmedchem.6b00564


Author Busnelli, Marta
Kleinau, Gunnar
Muttenthaler, Markus
Stoev, Stoytcho
Manning, Maurice
Bibic, Lucka
Howell, Lesley A.
McCormick, Peter J.
Di Lascio, Simona
Braida, Daniela
Sala, Mariaelvina
Rovati, G. Enrico
Bellini, Tommaso
Chini, Bice
Title Design and characterization of superpotent bivalent ligands targeting oxytocin receptor dimers via a channel-like structure
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 1520-4804
0022-2623
Publication date 2016-08-11
Year available 2016
Sub-type Article (original research)
DOI 10.1021/acs.jmedchem.6b00564
Open Access Status Not yet assessed
Volume 59
Issue 15
Start page 7152
End page 7166
Total pages 15
Place of publication Washington, DC, United States
Publisher American Chemical Society
Language eng
Subject 1313 Molecular Medicine
3002 Drug Discovery
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.
Formatted 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.
Keyword Protein-Coupled Receptors
Single-Molecule Analysis
Crystal-Structure
Allosteric Interactions
Beta(2)-Adrenergic Receptor
Erk1/2 Activation
Social-Behavior
In-Vitro
Agonists
Gpcr
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID GGP12207
18099/RCC
254897
DE150100784
KL2334/2-2
2014_A114
GM-25280
MCCORMICK_U15DTP1
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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