Exploring the free-energy landscape of GPCR activation

Raphael Alhadeff, Igor Vorobyov, Han Wool Yoon, Arieh Warshel

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

G-protein-coupled receptors (GPCRs) are a large group of membranebound receptor proteins that are involved in a plethora of diverse processes (e.g., vision, hormone response). In mammals, and particularly in humans, GPCRs are involved in many signal transduction pathways and, as such, are heavily studied for their immense pharmaceutical potential. Indeed, a large fraction of drugs target various GPCRs, and drug-development is often aimed at GPCRs. Therefore, understanding the activation of GPCRs is a challenge of major importance both from fundamental and practical considerations. And yet, despite the remarkable progress in structural understanding, we still do not have a translation of the structural information to an energy-based picture. Herewe use coarse-grained (CG) modeling to chart the free-energy landscape of the activation process of the β-2 adrenergic receptor (β2AR) as a representative GPCR. The landscape provides the needed tool for analyzing the processes that lead to activation of the receptor upon binding of the ligand (adrenaline) while limiting constitutive activation. Our results pave the way to better understand the biological mechanisms of action of the β2AR and GPCRs, from a physical chemistry point of view rather than simply by observing the receptor's behavior physiologically.

Original languageEnglish (US)
Pages (from-to)10327-10332
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number41
DOIs
StatePublished - Oct 9 2018

Keywords

  • G protein
  • GPCR
  • Signal transduction
  • β2AR

ASJC Scopus subject areas

  • General

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