| Autor: |
Matthias Irmen, Janine Holze, Michael Kauk, Marcel Bermudez, Marco De Amici, Clelia Dallanoce, Klaus Mohr, Theresa Bödefeld, Gabriele M. König, Andreas Bock, Eva Marie Pfeil, Carsten Hoffmann, Gerhard Wolber, Carlo Matera, Ulrike Holzgrabe, Evi Kostenis, Ramona Schrage, Christian Tränkle |
| Rok vydání: |
2020 |
| Předmět: |
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| Zdroj: |
ACS Pharmacol Transl Sci |
| ISSN: |
2575-9108 |
| DOI: |
10.1021/acsptsci.0c00069 |
| Popis: |
[Image: see text] Allosteric coupling describes a reciprocal process whereby G-protein-coupled receptors (GPCRs) relay ligand-induced conformational changes from the extracellular binding pocket to the intracellular signaling surface. Therefore, GPCR activation is sensitive to both the type of extracellular ligand and intracellular signaling protein. We hypothesized that ligand-specific allosteric coupling may result in preferential (i.e., biased) engagement of downstream effectors. However, the structural basis underlying ligand-dependent control of this essential allosteric mechanism is poorly understood. Here, we show that two sets of extended muscarinic acetylcholine receptor M(1) agonists, which only differ in linker length, progressively constrain receptor signaling. We demonstrate that stepwise shortening of their chemical linker gradually hampers binding pocket closure, resulting in divergent coupling to distinct G-protein families. Our data provide an experimental strategy for the design of ligands with selective G-protein recognition and reveal a potentially general mechanism of ligand-specific allosteric coupling. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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