Targeting G protein-coupled receptor signaling at the G protein level with a selective nanobody inhibitor

Sahil Gulati, Hui Jin, Ikuo Masuho, Tivadar Orban, Yuan Cai, Els Pardon, Kirill A. Martemyanov, Philip D. Kiser, Phoebe L. Stewart, Christopher P. Ford, Jan Steyaert and Krzysztof Palczewski ()
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Sahil Gulati: Case Western Reserve University
Hui Jin: Case Western Reserve University
Ikuo Masuho: The Scripps Research Institute
Tivadar Orban: Case Western Reserve University
Yuan Cai: Case Western Reserve University
Els Pardon: Vrije Universiteit Brussel (VUB)
Kirill A. Martemyanov: The Scripps Research Institute
Philip D. Kiser: Case Western Reserve University
Phoebe L. Stewart: Case Western Reserve University
Christopher P. Ford: University of Colorado School of Medicine
Jan Steyaert: Vrije Universiteit Brussel (VUB)
Krzysztof Palczewski: Case Western Reserve University

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract G protein-coupled receptors (GPCRs) activate heterotrimeric G proteins by mediating a GDP to GTP exchange in the Gα subunit. This leads to dissociation of the heterotrimer into Gα-GTP and Gβγ dimer. The Gα-GTP and Gβγ dimer each regulate a variety of downstream pathways to control various aspects of human physiology. Dysregulated Gβγ-signaling is a central element of various neurological and cancer-related anomalies. However, Gβγ also serves as a negative regulator of Gα that is essential for G protein inactivation, and thus has the potential for numerous side effects when targeted therapeutically. Here we report a llama-derived nanobody (Nb5) that binds tightly to the Gβγ dimer. Nb5 responds to all combinations of β-subtypes and γ-subtypes and competes with other Gβγ-regulatory proteins for a common binding site on the Gβγ dimer. Despite its inhibitory effect on Gβγ-mediated signaling, Nb5 has no effect on Gαq-mediated and Gαs-mediated signaling events in living cells.

Date: 2018
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DOI: 10.1038/s41467-018-04432-0

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