A high-resolution description of β1-adrenergic receptor functional dynamics and allosteric coupling from backbone NMR
| Autor: | Grahl, Anne, Abiko, Layara Akemi, Isogai, Shin, Sharpe, Timothy, Grzesiek, Stephan |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular inorganic chemicals Magnetic Resonance Spectroscopy Protein Conformation Science Models Theoretical Spodoptera Ligands Biochemistry Article Receptors G-Protein-Coupled NMR spectroscopy Allosteric Regulation biological sciences Sf9 Cells Animals Humans lcsh:Q Receptors Adrenergic beta-1 lcsh:Science Algorithms Protein Binding |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-13 (2020) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | Signal transmission and regulation of G-protein-coupled receptors (GPCRs) by extra- and intracellular ligands occurs via modulation of complex conformational equilibria, but their exact kinetic details and underlying atomic mechanisms are unknown. Here we quantified these dynamic equilibria in the β1-adrenergic receptor in its apo form and seven ligand complexes using 1H/15N NMR spectroscopy. We observe three major exchanging conformations: an inactive conformation (Ci), a preactive conformation (Cp) and an active conformation (Ca), which becomes fully populated in a ternary complex with a G protein mimicking nanobody. The Ci ↔ Cp exchange occurs on the microsecond scale, the Cp ↔ Ca exchange is slower than ~5 ms and only occurs in the presence of two highly conserved tyrosines (Y5.58, Y7.53), which stabilize the active conformation of TM6. The Cp→Ca chemical shift changes indicate a pivoting motion of the entire TM6 that couples the effector site to the orthosteric ligand pocket. Signal transmission and regulation of G-protein-coupled receptors (GPCRs) by ligands occurs via modulation of complex conformational equilibria. Here authors quantify these equilibria and their dynamics in the β1-adrenergic receptor in its apo form and seven ligand complexes using NMR. |
| Databáze: | OpenAIRE |
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