New Cell paper marks deepening understanding of GPCRs

17 June 2016

The ongoing work at MIPS to better understand signalling pathways within the G protein-coupled receptor (GPCR) family has passed another milestone with the publication today of a paper in the highly regarded journal Cell.

Led by Dr Denise Wootten and Professor Patrick Sexton, the research will ultimately aid in the development of more effective drugs with increased selectivity and fewer side effects.

The paper focuses on ‘biased agonism’. Biased agonism is a phenomenon whereby different molecules that the body uses to communicate between cells (the ‘ligands’) acting at the same specific target on the cell’s surface (the ‘receptor’) can elicit different outcomes  within the same cell.

Dr Wootten and Dr Sexton’s research observes the effect of three separate ligands on a GPCR that is a major target for the treatment of type-2 diabetes, the glucagon-like peptide-1 receptor.

The work provides novel insight into how different ligands, both naturally occurring and those used clinically, interact with their target receptor and how this allows differential engagement of the receptor with effector proteins within the cell.

Through collaboration with Prof Christopher Reynolds and his team at the University of Essex, the initial molecular triggers for activation have been mapped onto 3D models of the receptor, providing deeper understanding of how different parts of the ligands drive distinct signalling.

This new work provides a template for future design of more effective therapeutics at this clinically important receptor.

Dr Wootten and Professor Sexton talk about their research in more detail in the video below.