The importance of ligands for G protein-coupled receptor stability

Xianjun Zhang; Raymond C Stevens; Fei Xu

doi:10.1016/j.tibs.2014.12.005

The importance of ligands for G protein-coupled receptor stability

Trends Biochem Sci. 2015 Feb;40(2):79-87. doi: 10.1016/j.tibs.2014.12.005. Epub 2015 Jan 15.

Authors

Xianjun Zhang¹, Raymond C Stevens¹, Fei Xu²

Affiliations

¹ iHuman Institute, ShanghaiTech University, 2F Building 6, 99 Haike Road, Pudong New District, Shanghai, 201210, China.
² iHuman Institute, ShanghaiTech University, 2F Building 6, 99 Haike Road, Pudong New District, Shanghai, 201210, China. Electronic address: xufei@shanghaitech.edu.cn.

PMID: 25601764
DOI: 10.1016/j.tibs.2014.12.005

Abstract

Traditionally, G protein-coupled receptor (GPCR) activity has been characterized by ligand properties including affinity (Ki), potency (IC50/EC50), efficacy (Emax), and kinetics (Kon/Koff). These properties are related to ligand residence time, a general index of drug-target interaction in vivo. Recent GPCR structure-function breakthroughs have all required ligand stabilization of the receptor in some manner, highlighting the natural instability of these important cell surface receptors. This research has initiated a new era of discovery that highlights the importance of ligand-receptor interactions beyond the traditional mindset. We propose that receptor stability is related to receptor folding and residence in the cell membrane, affording a new dimension that should be considered when studying receptor function.

Keywords: GPCR stabilization; ligand residence time; receptor residence time.

Publication types

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

MeSH terms

Cell Membrane / chemistry
Cell Membrane / metabolism
Kinetics
Ligands*
Protein Binding
Receptors, G-Protein-Coupled / chemistry
Receptors, G-Protein-Coupled / metabolism*
Structure-Activity Relationship*

Substances

Ligands
Receptors, G-Protein-Coupled