Format

Send to

Choose Destination
Nat Commun. 2018 May 18;9(1):1996. doi: 10.1038/s41467-018-04432-0.

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

Author information

1
Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA.
2
Cleveland Center for Membrane and Structural Biology, Case Western Reserve University, 1819 East 101st Street, Cleveland, OH, 44106, USA.
3
Department of Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33458, USA.
4
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH, 44106, USA.
5
Department of Pharmacology, University of Colorado School of Medicine, 12800 East 19th Ave, Aurora, CO, 80045, USA.
6
Structural Biology Brussels, Vrije Universiteit Brussel (VUB), Brussels, 1050, Belgium.
7
VIB-VUB Center for Structural Biology, VIB, Brussels, 1050, Belgium.
8
Research Service, Louis Stokes Cleveland VA Medical Center, Cleveland, OH, 44106, USA.
9
Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA. kxp65@case.edu.
10
Cleveland Center for Membrane and Structural Biology, Case Western Reserve University, 1819 East 101st Street, Cleveland, OH, 44106, USA. kxp65@case.edu.

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.

PMID:
29777099
PMCID:
PMC5959942
DOI:
10.1038/s41467-018-04432-0
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center