New method for activating GPCRs could lead to more effective and safer drugs

Researchers from the University of Tokyo have made a significant discovery regarding G protein-coupled receptors (GPCRs), which play a crucial role in relaying molecular signals in our bodies. GPCRs are involved in about one-third of existing drugs, but their activation can lead to adverse side effects by activating multiple signaling pathways. To address this issue, the researchers sought to activate GPCRs from inside the cell, rather than outside, in order to achieve specificity and minimize side effects.

The team, led by Professor Osamu Nureki, focused on a GPCR called the human parathyroid hormone type 1 receptor (PTH1R), which is related to bone metabolism and is a target for osteoporosis treatment. They used cryo-electron microscopy to examine the 3D structure of PTH1R and the G protein bound to a message molecule. Through their investigations, they synthesized a non-peptide message molecule called PCO371, which directly binds to the intracellular region of the receptor and interacts with G protein subunits, thus activating the receptor after entering the cell.

The structure of PTH1R bound to PCO371 was found to modulate the intracellular side of the receptor in a direct and stable manner. Importantly, PCO371 specifically activates the G protein pathway and does not activate the ß-arrestin pathway, thereby avoiding side effects. This selective binding and activation mechanism make PCO371 a promising candidate for the development of small-molecule-based drugs that target class B1 GPCRs like PTH1R, which currently lack oral administration options. By targeting specific molecular pathways, such drugs could reduce adverse effects and be more convenient for patients.

The research findings are expected to contribute to the development of new drugs for various disorders, including obesity, pain, osteoporosis, and neurological disorders. The study, conducted by doctoral student Kazuhiro Kobayashi and his team, was published in the journal Nature.

Source: University of Tokyo

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