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Unraveling allostery within the angiotensin II type 1 receptor for Gα q and β-arrestin coupling.

Yubo CaoWijnand J C van der VeldenYoon NamkungAnita K NivedhaAaron ChoDana SedkiBrian HolleranNicholas LeeRichard LeducSanychen MukKeith LeSupriyo BhattacharyaNagarajan VaidehiStéphane A Laporte
Published in: Science signaling (2023)
G protein-coupled receptors engage both G proteins and β-arrestins, and their coupling can be biased by ligands and mutations. Here, to resolve structural elements and mechanisms underlying effector coupling to the angiotensin II (AngII) type 1 receptor (AT1R), we combined alanine scanning mutagenesis of the entire sequence of the receptor with pharmacological profiling of Gα q and β-arrestin engagement to mutant receptors and molecular dynamics simulations. We showed that Gα q coupling to AT1R involved a large number of residues spread across the receptor, whereas fewer structural regions of the receptor contributed to β-arrestin coupling regulation. Residue stretches in transmembrane domain 4 conferred β-arrestin bias and represented an important structural element in AT1R for functional selectivity. Furthermore, we identified allosteric small-molecule binding sites that were enclosed by communities of residues that produced biased signaling when mutated. Last, we showed that allosteric communication within AT1R emanating from the Gα q coupling site spread beyond the orthosteric AngII-binding site and across different regions of the receptor, including currently unresolved structural regions. Our findings reveal structural elements and mechanisms within AT1R that bias Gα q and β-arrestin coupling and that could be harnessed to design biased receptors for research purposes and to develop allosteric modulators.
Keyphrases
  • angiotensin ii
  • small molecule
  • room temperature
  • molecular dynamics simulations
  • vascular smooth muscle cells
  • crispr cas
  • dna methylation
  • dendritic cells
  • mass spectrometry