AsianScientist (Aug. 7, 2015) – Using one of the brightest X-ray lasers in the world, researchers have determined the structure of a molecular complex that is responsible for regulating the vital physiological functions: G-protein-coupled receptors (GPCRs). Their research, published in Nature, provide scientists with a new model for major pharmacological drug targets.
“GPCRs are major targets in the development of new therapies and account for almost 40 percent of current drug targets”, said Dr. H. Eric Xu, a professor from Shanghai Institute of Materia Medica, Chinese Academy of Sciences.
“In the realm of drug development, a detailed understanding of the structure, interaction and function of each of these groups of proteins is vital to developing effective therapies. The more specific the interaction, the better the drugs tend to work while also lowering the chance of side effects.”
Despite the importance of GPCRs in many biological processes, their precise three-dimensional structure is still a largely unconquered area. Over the last decade, a team led by Xu has worked to unravel the structure of a complex made up of arrestin and rhodopsin, which is a prototypical GPCR responsible for light perception and activating visual function.
The most challenging issue is that the tiny arrestin-GPCR crystals, which Xu’s team had painstakingly produced over years, proved too difficult to study at even the most advanced type of synchrotron, a more conventional X-ray source. By using a x-ray free-electron laser (XFEL)—the brightest laser in the world—Xu and his team determined the three-dimensional image of Rhodopsin-arrestin complex at an atomic level.
The structure reveals an overall architecture of the rhodopsin-arrestin assembly, in which arrestin uses distinct interaction mode compared with G protein.
“Our work shows that arrestin and G proteins play Yin (negative) and Yang (positive) roles in regulating GPCR function,” Xu added.
This structure provides a basis for understanding GPCR-mediated arrestin-biased signaling and demonstrates the power of X-ray lasers for advancing the frontiers of structural biology.
The article can be found at: Kang et al. (2015) Crystal Structure of Rhodopsin Bound to Arrestin by Femtosecond X-ray Laser.
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Source: Shanghai Institutes for Biological Sciences.
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