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G protein-coupled receptors (GPCRs) represent the largest group of membrane receptors for transmembrane signal transduction. Ligand-induced activation of GPCRs triggers G protein activation followed by various signaling cascades. Understanding the structural and energetic determinants of ligand binding to GPCRs and GPCRs to G proteins is crucial to the design of pharmacological treatments targeting specific conformations of these proteins to precisely control their signaling properties. In this study, we focused on interactions of a prototypical GPCR, beta-2 adrenergic receptor (β 2 AR), with its endogenous agonist, norepinephrine (NE), and the stimulatory G protein (G s ). Using molecular dynamics (MD) simulations, we demonstrated the stabilization of cationic NE, NE(+), binding to β 2 AR by G s protein recruitment, in line with experimental observations. We also captured the partial dissociation of the ligand from β 2 AR and the conformational interconversions of G s between closed and open conformations in the NE(+)–β 2 AR–G s ternary complex while it is still bound to the receptor. The variation of NE(+) binding poses was found to alter G s α subunit (G s α) conformational transitions. Our simulations showed that the interdomain movement and the stacking of G s α α1 and α5 helices are significant for increasing the distance between the G s α and β 2 AR, which may indicate a partial dissociation of G s α The distance increase commences when G s α is predominantly in an open state and can be triggered by the intracellular loop 3 (ICL3) of β 2 AR interacting with G s α, causing conformational changes of the α5 helix. Our results help explain molecular mechanisms of ligand and GPCR-mediated modulation of G protein activation.
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A free‐energy landscape for the glucagon‐like peptide 1 receptor GLP1R
Abstract G‐protein‐coupled receptors (GPCRs) are among the most important receptors in human physiology and pathology. They serve as master regulators of numerous key processes and are involved in as well as cause debilitating diseases. Consequently, GPCRs are among the most attractive targets for drug design and pharmaceutical interventions (>30% of drugs on the market). The glucagon‐like peptide 1 (GLP‐1) hormone receptor GLP1R is closely involved in insulin secretion by pancreatic β‐cells and constitutes a major druggable target for the development of anti‐diabetes and obesity agents. GLP1R structure was recently solved, with ligands, allosteric modulators and as part of a complex with its cognate G protein. However, the translation of this structural data into structure/function understanding remains limited. The current study functionally characterizes GLP1R with special emphasis on ligand and cellular partner binding interactions and presents a free‐energy landscape as well as a functional model of the activation cycle of GLP1R. Our results should facilitate a deeper understanding of the molecular mechanism underlying GLP1R activation, forming a basis for improved development of targeted therapeutics for diabetes and related disorders.
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- Award ID(s):
- 1707167
- PAR ID:
- 10459772
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Proteins: Structure, Function, and Bioinformatics
- Volume:
- 88
- Issue:
- 1
- ISSN:
- 0887-3585
- Page Range / eLocation ID:
- p. 127-134
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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