2. Academic Validation
  3. Structural basis of adenosine 2A receptor-balanced signaling activation relies on allosterically mediated structural dynamics

Structural basis of adenosine 2A receptor-balanced signaling activation relies on allosterically mediated structural dynamics

  • Cell Chem Biol. 2025 Sep 18;32(9):1140-1149.e3. doi: 10.1016/j.chembiol.2025.08.005.
Canyong Guo 1,  Lingyun Yang 2,  Junlin Liu 2,  Dongsheng Liu 1,  Kurt Wüthrich 3
Affiliations

Affiliations

  • 1 iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 2 iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
  • 3 iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Department of Integrative Structural and Computational Biology, Scripps Research, La Jolla, CA 92037, USA; Institute of Molecular Biology and Biophysics, ETH Zürich, Otto-Stern-Weg 5, 8093 Zürich, Switzerland. Electronic address: wuthrich@shanghaitech.edu.cn.
PMID: 40925370 DOI: 10.1016/j.chembiol.2025.08.005
Abstract

Balanced or biased G protein and Arrestin transmembrane signaling by the adenosine 2A receptor (A2AAR) is related to ligand-induced allosterically triggered variation of structural dynamics in the intracellular half of the transmembrane domain (TMD). 19F-nuclear magnetic resonance (NMR) of a network of genetically introduced meta-trifluoromethyl-L-phenylalanine (mtfF) probes in the core of the TMD revealed signaling-related structure rearrangements leading from the extracellular orthosteric drug-binding site to the G protein and Arrestin contacts on the intracellular surface. The key element in this structural basis of signal transfer is dynamic loss of structural order in the intracellular half of the TMD, as manifested by local polymorphisms and associated rate processes within the molecular architecture determined previously by X-ray crystallography. This visualization of the structural basis of G protein-coupled receptor (GPCR) activation presents an alternative paradigm for optimizing biased signaling in drug design.

Keywords

(19)F-NMR probes; GPCR; NMR spectroscopy; adenosine A(2A) receptor; allosteric signal transfer; structural dynamics.

Figures
Products