Arrestin development: X-ray laser signalling clues

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  • Published: Aug 1, 2015
  • Author: David Bradley
  • Channels: X-ray Spectrometry
thumbnail image: Arrestin development: X-ray laser signalling clues

Arrestin details

Arrestin (yellow), an important signalling protein docked with rhodopsin (orange), a G protein-coupled receptor. GPCRs are embedded in cell membranes and serve roles in cellular signalling (Credit: SLAC National Accelerator Laboratory)

New details of an integral component in the human body’s cellular switchboard that regulates sensory and hormonal responses have been revealed by scientists using SLAC's ultrabright femtosecond X-ray laser. The discovery could have broad implications on the development of more highly targeted and effective drugs with fewer side effects for high blood pressure, diabetes, depression, and even some types of cancer.

Scientists at the Van Andel Research Institute in Michigan worked with dozens of other researchers from around the globe on the discovery that has been ten years in the making. The ultrabright source allowed the research team to complete the first three-dimensional, atomic-scale map of the signalling protein, arrestin while it was docked with a cell receptor involved in vision. The receptor is a well-studied example from a family of hundreds of G protein-coupled receptors, or GPCRs, which are targeted by about 40 percent of drugs on the market. Its structure while coupled with arrestin provides new insight into the way in which on-off signalling pathways among GPCRs work.


Arrestins and the G proteins take turns docking with GPCRs, both playing an essential part in chemical communications within the body acting as the components of a cellular "switchboard" sending signals that the receptors translate into cell instructions responsible for a range of physiological functions. Until now, only a G protein had been docked to a receptor at this resolution and little was known about how arrestins - the "off" switch protein to the G proteins "on" - dock with GPCRs, and how this differs from G protein docking. The new study reveals fine details about the process with arrestin.

"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," explains team leader Eric Xu. In the experiments, Xu's team used samples of human rhodopsin - a retinal GPCR - fused to mouse arrestin that is very similar to human arrestin. "While this particular sample serves a specific function in the body, people may start to use this research as a model for how GPCRs, in general, can interact with signalling proteins," Xu adds. His team have been working towards this experiment since 2005.

"This structure is especially important because it fills in a missing piece about protein-binding pathways for GPCRs," explains team member Qingping Xu. He notes, however, that much work remains to be done in the determination of the unique structures and docking mechanisms of the many other signalling proteins.

International effort

In addition to the SLAC researchers, scientists from Arizona State University, University of Southern California, DESY Lab's Center for Free Electron Laser Science in Germany, National University of Singapore, New York Structural Biology Center, The Scripps Research Institute, University of California, Los Angeles, University of Toronto, Vanderbilt University, Beijing Computational Science Research Center in China, University of Wisconsin-Milwaukee, Chinese Academy of Sciences, Paul Scherrer Institute, Switzerland, Trinity College, Ireland, University of Chicago, University of Konstanz, Germany, Chinese Academy of Sciences, Center for Ultrafast Imaging, Germany, and University of Toronto, were all involved in the research.

Related Links

Nature 2015, 523, 561-567: "Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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