What is it about?

We develop a new cell-free assay to monitor GPCR molecular efficacy. We use the new tool to provide structural insights into function of distinct GPCR-G protein complex orientation.

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Why is it important?

An outstanding challenge in GPCR pharmacology is quantifying the system-independent functional effects of ligand-receptor interactions. Current efforts to measure ligand efficacy at the level of the receptor (i.e. molecular efficacy) are limited by the requirement of extensive purification of receptor and G proteins to homogeneity. In this study, we present an accessible, scalable technology for the single point measurement of the molecular efficacy of GPCR ligands. Integrating this technology with insights from molecular dynamics simulations, we reveal that the transition of the G protein from an intermediate to a fully coupled interaction with the GPCR is a novel structural determinant of ligand molecular efficacy.

Perspectives

We have a way to monitor GPCR ligand molecular efficacy without GPCR purification. As GPCR purification is not accessible to most of the GPCR community, it will be a valuable tool. We also shed light into the function of the recently discovered b2AR-GaS intermediate orientation how molecular efficacy is determined.

Keehun Kim
University of Minnesota Twin Cities

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This page is a summary of: β2-adrenoceptor ligand efficacy is tuned by a two-stage interaction with the Gαs C terminus, Proceedings of the National Academy of Sciences, March 2021, Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.2017201118.
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