DEER Analysis of GPCR Conformational Heterogeneity
G protein-coupled receptors (GPCRs) represent a large class of transmembrane helical proteins which are involved in numerous physiological signaling pathways and therefore represent crucial pharmacological targets. GPCR function and the action of therapeutic molecules are defined by only a few param...
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doaj-991163fe50b14ef7b1f532410bbca46e2021-06-01T00:47:38ZengMDPI AGBiomolecules2218-273X2021-05-011177877810.3390/biom11060778DEER Analysis of GPCR Conformational HeterogeneityMatthias Elgeti0Wayne L. Hubbell1Jules Stein Eye Institute and Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095, USAJules Stein Eye Institute and Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095, USAG protein-coupled receptors (GPCRs) represent a large class of transmembrane helical proteins which are involved in numerous physiological signaling pathways and therefore represent crucial pharmacological targets. GPCR function and the action of therapeutic molecules are defined by only a few parameters, including receptor basal activity, ligand affinity, intrinsic efficacy and signal bias. These parameters are encoded in characteristic receptor conformations existing in equilibrium and their populations, which are thus of paramount interest for the understanding of receptor (mal-)functions and rational design of improved therapeutics. To this end, the combination of site-directed spin labeling and EPR spectroscopy, in particular double electron–electron resonance (DEER), is exceedingly valuable as it has access to sub-Angstrom spatial resolution and provides a detailed picture of the number and populations of conformations in equilibrium. This review gives an overview of existing DEER studies on GPCRs with a focus on the delineation of structure/function frameworks, highlighting recent developments in data analysis and visualization. We introduce “conformational efficacy” as a parameter to describe ligand-specific shifts in the conformational equilibrium, taking into account the loose coupling between receptor segments observed for different GPCRs using DEER.https://www.mdpi.com/2218-273X/11/6/778G protein-coupled receptorGPCR7TM receptorG proteinarrestinstructure |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Matthias Elgeti Wayne L. Hubbell |
spellingShingle |
Matthias Elgeti Wayne L. Hubbell DEER Analysis of GPCR Conformational Heterogeneity Biomolecules G protein-coupled receptor GPCR 7TM receptor G protein arrestin structure |
author_facet |
Matthias Elgeti Wayne L. Hubbell |
author_sort |
Matthias Elgeti |
title |
DEER Analysis of GPCR Conformational Heterogeneity |
title_short |
DEER Analysis of GPCR Conformational Heterogeneity |
title_full |
DEER Analysis of GPCR Conformational Heterogeneity |
title_fullStr |
DEER Analysis of GPCR Conformational Heterogeneity |
title_full_unstemmed |
DEER Analysis of GPCR Conformational Heterogeneity |
title_sort |
deer analysis of gpcr conformational heterogeneity |
publisher |
MDPI AG |
series |
Biomolecules |
issn |
2218-273X |
publishDate |
2021-05-01 |
description |
G protein-coupled receptors (GPCRs) represent a large class of transmembrane helical proteins which are involved in numerous physiological signaling pathways and therefore represent crucial pharmacological targets. GPCR function and the action of therapeutic molecules are defined by only a few parameters, including receptor basal activity, ligand affinity, intrinsic efficacy and signal bias. These parameters are encoded in characteristic receptor conformations existing in equilibrium and their populations, which are thus of paramount interest for the understanding of receptor (mal-)functions and rational design of improved therapeutics. To this end, the combination of site-directed spin labeling and EPR spectroscopy, in particular double electron–electron resonance (DEER), is exceedingly valuable as it has access to sub-Angstrom spatial resolution and provides a detailed picture of the number and populations of conformations in equilibrium. This review gives an overview of existing DEER studies on GPCRs with a focus on the delineation of structure/function frameworks, highlighting recent developments in data analysis and visualization. We introduce “conformational efficacy” as a parameter to describe ligand-specific shifts in the conformational equilibrium, taking into account the loose coupling between receptor segments observed for different GPCRs using DEER. |
topic |
G protein-coupled receptor GPCR 7TM receptor G protein arrestin structure |
url |
https://www.mdpi.com/2218-273X/11/6/778 |
work_keys_str_mv |
AT matthiaselgeti deeranalysisofgpcrconformationalheterogeneity AT waynelhubbell deeranalysisofgpcrconformationalheterogeneity |
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