Isoform- and ligand-specific modulation of the adhesion GPCR ADGRL3/Latrophilin3 by a synthetic binder

Szymon P. Kordon, Przemysław Dutka, Justyna M. Adamska, Sumit J. Bandekar, Katherine Leon, Satchal K. Erramilli, Brock Adams, Jingxian Li, Anthony A. Kossiakoff and Demet Araç ()
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Szymon P. Kordon: The University of Chicago
Przemysław Dutka: The University of Chicago
Justyna M. Adamska: The University of Chicago
Sumit J. Bandekar: The University of Chicago
Katherine Leon: The University of Chicago
Satchal K. Erramilli: The University of Chicago
Brock Adams: The University of Chicago
Jingxian Li: The University of Chicago
Anthony A. Kossiakoff: The University of Chicago
Demet Araç: The University of Chicago

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Adhesion G protein-coupled receptors (aGPCRs) are cell-surface proteins with large extracellular regions that bind to multiple ligands to regulate key biological functions including neurodevelopment and organogenesis. Modulating a single function of a specific aGPCR isoform while affecting no other function and no other receptor is not trivial. Here, we engineered an antibody, termed LK30, that binds to the extracellular region of the aGPCR ADGRL3, and specifically acts as an agonist for ADGRL3 but not for its isoform, ADGRL1. The LK30/ADGRL3 complex structure revealed that the LK30 binding site on ADGRL3 overlaps with the binding site for an ADGRL3 ligand – teneurin. In cellular-adhesion assays, LK30 specifically broke the trans-cellular interaction of ADGRL3 with teneurin, but not with another ADGRL3 ligand – FLRT3. Our work provides proof of concept for the modulation of isoform- and ligand-specific aGPCR functions using unique tools, and thus establishes a foundation for the development of fine-tuned aGPCR-targeted therapeutics.

Date: 2023
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DOI: 10.1038/s41467-023-36312-7

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