Molecular mechanism of biased signaling in a prototypical G protein-coupled receptor
| Autor: | Alissa L. W. Kleinhenz, Matthew C. King, Naomi R. Latorraca, Carl-Mikael Suomivuori, Robert J. Lefkowitz, Stephan Eismann, Ron O. Dror, Meredith A. Skiba, Andrew C. Kruse, Laura M. Wingler, Dean P. Staus |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Multidisciplinary G protein Chemistry Arrestins Protein Conformation Allosteric regulation Molecular Dynamics Simulation Angiotensin II Article Receptor Angiotensin Type 1 Cell biology 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Protein structure Allosteric Regulation GTP-Binding Proteins Arrestin Humans Signal transduction Receptor 030217 neurology & neurosurgery G protein-coupled receptor Signal Transduction |
| Zdroj: | Science |
| Popis: | Choosing the drug to fit the protein Many approved drugs bind to G protein–coupled receptors (GPCRs). A challenge in targeting GPCRs is that different ligands preferentially activate different signaling pathways. Two papers show how biased signaling arises for the angiotensin II type 1 receptor that couples to two signaling partners (G proteins and arrestins). Suomivuori et al. used large-scale atomistic simulations to show that coupling to the two pathways is through two distinct GPCR conformations and that extracellular ligands favor one or the other conformation. Wingler et al. present crystal structures of the same receptor bound to ligands with different bias profiles. These structures show conformational changes in and around the binding pocket that match those observed in simulations. This work could provide a framework for the rational design of drugs that are more effective and have fewer side effects. Science , this issue p. 881 , p. 888 |
| Databáze: | OpenAIRE |
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