Scientists determine structure of important drug target using groundbreaking approach

GRAND RAPIDS, Mich. (July 22, 2015) Using the brightest X-ray laser in the world, scientists have determined the structure of a molecular complex that is responsible for regulating vital physiological functions, and that serves as a major pharmacological drug target.

The new findings provide scientists with a roadmap for more selectively targeting pathways for drug treatment, which may lead to more effective therapies with fewer side effects for diseases such as cancer, heart disease and neurodegenerative disorders. The study, Crystal structure of rhodopsin bound to arrestin determined by femtosecond X-ray laser, was published online today in the journal Nature.

For the last decade, a team led by Van Andel Research Institute’s (VARI) H. Eric Xu, Ph.D., the paper’s senior author, has worked to unravel the structure of a complex made up of a signaling protein called arrestin, which plays a vital role in cellular communication, and a G protein-coupled receptor (GPCR) called rhodopsin. Arrestin, as well as other signaling proteins known as G proteins, link up with GPCRs to convey important instructions for many essential physiological functions, such as growth and hormone regulation. G protein and arrestin pathways are physiologically distinct; GPCR drugs that selectively modulate one pathway are often preferred as they can have better therapeutic benefits with fewer undesirable side effects than non-selective drugs.

The X-ray laser work was conducted at the Department of Energy’s SLAC National Accelerator Laboratory, which is operated by Stanford University. Xu and his team utilized SLAC’s Linac Coherent Light Source (LCLS), the world’s first hard X-ray free electron laser, to generate the first three-dimensional map of arrestin while it was linked with a GPCR. LCLS boasts X-ray pulses that are a billion times brighter than previous X-ray sources, and that last for miniscule fractions of a second. This capability allowed the team to create the three-dimensional image of the arrestin-rhodopsin complex at an atomic level—a much higher resolution than is possible with conventional X-ray technology.

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Video courtesy of SLAC National Accelerator Laboratory.

“Arrestin and G proteins are the yin and the yang of regulating GPCR function,” Xu said. “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.”

GPCRs make up the largest group of cell surface receptors and act as the information clearinghouse for cells by receiving “data” from external sources, which tells the cells about their environment and conveys information from nearby cells. Cell surface receptors are excellent therapeutic targets due to their location on the surface of the cell, making them more accessible to drug treatment. Given their central roles in cellular communication, GPCRs are major targets in the development of new therapies and account for about 40 percent of current drug targets.

Prior to this study, scientists knew little about how arrestin becomes bound to GPCRs, which switch a subset of cell signals on, and how this differed from interactions with G proteins, which activate different subsets of cell signals. A major breakthrough came in 2011 when a team led by scientists from Stanford University and University of Michigan reported the first structure of a G protein bound to a GPCR. Taken with the new work, the discoveries provide a basis for developing therapies that specifically activate the arrestin pathway or the G protein pathway, rather than both.

“The Xu group has put together an important story that provides significant insight into our understanding of G protein-coupled receptor function,” said Jeffrey Benovic, Ph.D., Thomas Eakins Professor at Thomas Jefferson University, a GPCR expert who was not involved in the study. “The rhodopsin-arrestin structure helps to explain the process of desensitization and provides a roadmap for obtaining the structure of additional GPCR complexes.”

Xu and his team have additional studies planned using LCLS, including uncovering the structures of protein complexes involved in the full GPCR signaling cycle and how small molecule drugs regulate this cycle.

“This project represented a significant challenge and was accomplished through the work of a multidisciplinary team from many institutions around the globe,” said Xu. “Utilizing the X-ray laser also opens the door for solving future challenging problems.”

The collaborative spirit of the project allowed the team to overcome many of the roadblocks that came along with determining the structure of the arrestin-rhodopsin complex, such as generating enough usable crystals and imaging the structure at a high enough resolution, said Yanyong Kang, Ph.D., a postdoctoral fellow in Xu’s lab. Kang, along with fellow Xu lab members X. Edward Zhou, Ph.D., Xiang Gao, Ph.D., and Yuanzheng He, Ph.D., are first authors on the paper.

“Obtaining this structure had its challenges in every step, from protein expression to purification and crystallization, and from data collection to structure determination and validation,” Kang said. “It is a tremendous experience for me to work on such a significant project and I am so grateful for the extraordinary help from so many different experts, who together made this project a success.”

The work was conducted by Xu’s laboratory at VARI in collaboration with VARI’s Karsten Melcher, Ph.D., and collaborators across the globe, including Joint Center for Structural Genomics, Stanford Synchrotron Radiaton Lightsource; LCLS, SLAC National Accelerator Laboratory; VARI-Shanghai Institute of Materia Medica (VARI-SIMM), Chinese Academy of Science; Arizona State University; University of Southern California; University of California at Los Angeles; DESY’s Center for Free Electron Laser Science; University of Singapore; BioXFEL at University of Buffalo; BioXFEL at Arizona State University; The Scripps Research Institute; University of Toronto; Vanderbilt University; NSF Science and Technology Center; University of Wisconsin-Milwaukee; Paul Scherrer Institute; Trinity College Dublin; University of Chicago; Universität Konstanz; Chinese Academy of Sciences; Centre for Ultrafast Imaging; University of Toronto; and iHuman Institute, ShanghaiTech University.


Van Andel Institute (VAI) is an independent biomedical research and science education organization committed to improving the health and enhancing the lives of current and future generations. Established by Jay and Betty Van Andel in 1996 in Grand Rapids, Michigan, VAI has grown into a premier research and educational institution that supports the work of more than 270 scientists, educators and staff. Van Andel Research Institute (VARI), VAI’s research division, is dedicated to determining the epigenetic, genetic, molecular and cellular origins of cancer, Parkinson’s and other diseases and translating those findings into effective therapies. The Institute’s scientists work in on-site laboratories and participate in collaborative partnerships that span the globe. Learn more about Van Andel Institute or donate by visiting 100% To Research, Discovery & Hope®


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