Using ultra-bright X-rays at SLAC National Accelerator Laboratory, a team of international researchers has captured the 3-D structure of a key signaling protein and its receptor for the first time.
The discovery provides new insight into the functioning of a common cell receptor called a G protein-coupled receptor or GPCR. Researchers estimate this protein, and its relatives, are the targets of about 40 percent of pharmaceuticals. From a SLAC release:
“This work has tremendous therapeutic implications,” said Jeffrey Benovic, PhD, a biochemist who was not involved with the study. “The study is a critical first step and provides key insight into the structural interactions in these protein complexes.”
Specifically, the researchers were able to illuminate the structure of the GPCR bonded with a signaling protein called arrestin. Arrestins and G proteins both dock with the GPCRs, however, researchers had previously only examined a bonded G protein. G proteins are generally the "on" switch, while arrestins usually signal the GPCR to turn off:
Many of the available drugs that activate or deactivate GPCRs block both G proteins and arrestins from docking.
“The new paradigm in drug discovery is that you want to find this selective pathway – how to activate either the arrestin pathway or the G-protein pathway but not both — for a better effect,” said Eric Xu, PhD, a scientist at the Van Andel Research Institute in Michigan who led the experiment. The study notes that a wide range of drugs would likely be more effective and have fewer side effects with this selective activation.
Previously: Why Stanford Nobel Prize winner Brian Kobilka is a "tour de force of science", Funding basic science leads to clinical discoveries, eventually and Video of Brian Kobilka's Nobel lecture
Video by SLAC National Accelerator Laboratory
