| Autor: |
Stephan Eismann, Alissa L. W. Kleinhenz, Andrew C. Kruse, Ron O. Dror, Carl-Mikael Suomivuori, Meredith A. Skiba, Robert J. Lefkowitz, Laura M. Wingler, Dean P. Staus, Matthew C. King, Naomi R. Latorraca |
| Rok vydání: |
2020 |
| Předmět: |
|
| Zdroj: |
Biophysical Journal. 118:162a |
| ISSN: |
0006-3495 |
| DOI: |
10.1016/j.bpj.2019.11.1000 |
| Popis: |
Biased signaling, in which different ligands that bind to the same G protein-coupled receptor preferentially trigger distinct signaling pathways, holds great promise for the design of safer and more effective drugs. Its structural mechanism remains unclear, however, hampering efforts to design drugs with desired signaling profiles. Here, we use extensive atomic-level molecular dynamics simulations to determine how arrestin bias and G protein bias arise at the angiotensin II type 1 receptor. The receptor adopts two major signaling conformations, one of which couples almost exclusively to arrestin, whereas the other also couples effectively to a G protein. A long-range allosteric network allows ligands in the extracellular binding pocket to favor either of the two intracellular conformations. Guided by this computationally determined mechanism, we designed ligands with desired signaling profiles. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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