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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.
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Details
1 Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; Cleveland Center for Membrane and Structural Biology, Case Western Reserve University, Cleveland, OH, USA
2 Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
3 Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA
4 Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA
5 Structural Biology Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium; VIB-VUB Center for Structural Biology, VIB, Brussels, Belgium
6 Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; Research Service, Louis Stokes Cleveland VA Medical Center, Cleveland, OH, USA
7 Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA