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Exploring the free-energy landscape of GPCR activation.

ABSTRACT: G-protein-coupled receptors (GPCRs) are a large group of membrane-bound 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. Here we use coarse-grained (CG) modeling to chart the free-energy landscape of the activation process of the ?-2 adrenergic receptor (?2AR) 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 ?2AR and GPCRs, from a physical chemistry point of view rather than simply by observing the receptor's behavior physiologically.

SUBMITTER: Alhadeff R

PROVIDER: S-EPMC6187162 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Exploring the free-energy landscape of GPCR activation.

Alhadeff Raphael R Vorobyov Igor I Yoon Han Wool HW Warshel Arieh A

Proceedings of the National Academy of Sciences of the United States of America 20180926 41

G-protein-coupled receptors (GPCRs) are a large group of membrane-bound 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 GPCR ...[more]

PMID: 30257944

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Exploring the free-energy landscape of GPCR activation.

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Exploring the free-energy landscape of GPCR activation.

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