Novel way to develop drugs without side effects

A team of researchers headed by Osamu Nureki, a professor at the University of Tokyo, and his lab, discovered a new receptor activation mode of a bone metabolism-related GPCR called human parathyroid hormone type 1 receptor (PTH1R) without signal transduction from the extracellular side.

To understand function through structure, they used cryo-electron microscopy and revealed the 3D structure of the PTH1R and G protein bound to a message molecule. The team synthesized a non-peptide message molecule called PCO371 which binds to the intracellular region of the receptor and interacts directly with G protein subunits. In other words, PCO371 activates the receptor after entering the cell.

The PCO371-bound PTH1R structure can directly and stably modulate the intracellular side of PTH1R. And because PCO371 activates only G protein and not ß-arrestin it does not cause side effects.

Reference:

Class B1 GPCR activation by an intracellular agonist,Nature,DOI 10.1038/s41586-023-06169-3