A 19F-qNMR-Guided Mathematical Model for G Protein-Coupled Receptor Signaling
Giraldo, Jesús (Parc Taulí Hospital Universitari. Institut d'Investigació i Innovació Parc Taulí (I3PT))
Madsen, Jesper Jonasson (University of South Florida)
Wang, Xudong (University of South Florida)
Wang, Lei (University of Pittsburgh)
Zhang, Cheng (University of Pittsburgh)
Ye, Libin (University of South Florida)
Universitat Autònoma de Barcelona. Institut de Neurociències

Date:	2024
Abstract:	G protein-coupled receptors (GPCRs) exhibit a wide range of pharmacological efficacies, yet the molecular mechanisms responsible for the differential efficacies in response to various ligands remain poorly understood. This lack of understanding has hindered the development of a solid foundation for establishing a mathematical model for signaling efficacy. However, recent progress has been made in delineating and quantifying receptor conformational states and associating function with these conformations. This progress has allowed us to construct a mathematical model for GPCR signaling efficacy that goes beyond the traditional ON/OFF binary switch model. In this study, we present a quantitative conformation-based mathematical model for GPCR signaling efficacy using the adenosine A receptor (AR) as a model system, under the guide of F quantitative nuclear magnetic resonance experiments. This model encompasses two signaling states, a fully activated state and a partially activated state, defined as being able to regulate the cognate Ga nucleotide exchange with respective G protein recognition capacity. By quantifying the population distribution of each state, we can now in turn examine GPCR signaling efficacy. This advance provides a foundation for assessing GPCR signaling efficacy using a conformation-based mathematical model in response to ligand binding.
Grants:	Agencia Estatal de Investigación PID2020-119136RB-I00
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Language:	Anglès
Document:	Article ; recerca ; Versió acceptada per publicar
Subject:	Membrane Protein ; Conformational Ensemble ; Signaling Efficacy ; Mathematical Modeling ; NMR
Published in:	Molecular Pharmacology, Vol. 105, Núm. 1 (December 2024) , p. 54-62, ISSN 1521-0111

DOI: 10.1124/molpharm.123.000754
PMID: 37907352

Postprint 27 p, 1.4 MB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Parc Taulí Research and Innovation Institute (I3PT
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Neurociències (INc)
Articles > Research articles
Articles > Published articles