Selective targeting of ligand-dependent and -independent signaling by GPCR conformation-specific anti-US28 intrabodies

Timo W. M. De Groof, Nick D. Bergkamp, Raimond Heukers, Truc Giap, Maarten P. Bebelman, Richard Goeij- de Haas, Sander R. Piersma, Connie R. Jimenez, K. Christopher Garcia, Hidde L. Ploegh, Marco Siderius and Martine J. Smit ()
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Timo W. M. De Groof: VU University
Nick D. Bergkamp: VU University
Raimond Heukers: VU University
Truc Giap: VU University
Maarten P. Bebelman: VU University
Richard Goeij- de Haas: Amsterdam University Medical Center, VU University, Cancer Center Amsterdam
Sander R. Piersma: Amsterdam University Medical Center, VU University, Cancer Center Amsterdam
Connie R. Jimenez: Amsterdam University Medical Center, VU University, Cancer Center Amsterdam
K. Christopher Garcia: Stanford University School of Medicine
Hidde L. Ploegh: Boston Children’s Hospital
Marco Siderius: VU University
Martine J. Smit: VU University

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract While various GPCRs, including US28, display constitutive, ligand-independent activity, it remains to be established whether ligand-dependent and -independent active conformations differ and can be selectively modulated. Previously, the agonist-bound conformation of US28 was stabilized and its structure was solved using the anti-US28 nanobody Nb7. Here we report the recognition of the constitutively active, apo-conformation of US28 by another nanobody VUN103. While the Nb7 intrabody selectively inhibits ligand-induced signaling, the VUN103 intrabody blocks constitutive signaling, indicating the existence of distinct US28 conformational states. By displacing Gαq protein, VUN103 prevents US28 signaling and reduces tumor spheroids growth. Overall, nanobodies specific for distinct GPCR conformational states, i.e. apo- and agonist-bound, can selectively target and discern functional consequences of ligand-dependent versus independent signaling.

Date: 2021
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DOI: 10.1038/s41467-021-24574-y

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