Emerging structural insights into biased GPCR signaling

Trends Biochem Sci. 2014 Dec;39(12):594-602. doi: 10.1016/j.tibs.2014.10.001. Epub 2014 Nov 4.


The discovery of biased signaling at G protein-coupled receptors (GPCRs), the largest class of cell surface receptors and primary drug targets for numerous human diseases, has redefined the classical concepts of receptor pharmacology. It not only highlights the depth of signaling diversity within the GPCR system, but also offers possibilities for novel and more-effective therapeutics. Here, we highlight the recent biophysical and structural advances in our understanding of ligand-receptor interactions and conformational changes in the receptors, which provide novel mechanistic insights into biased GPCR signaling. We also underline key aspects of GPCR-biased signaling that remain to be investigated in greater detail to develop a complete molecular understanding of this process and overall GPCR signaling.

Keywords: G protein-coupled receptors (GPCRs); biased agonism; biased signaling; β-arrestin; β2 adrenergic receptor’.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Humans
  • Ligands
  • Models, Biological*
  • Models, Molecular*
  • Protein Conformation
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / antagonists & inhibitors
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction*


  • Ligands
  • Receptors, G-Protein-Coupled