Home / Node / Scientists determine structure of important drug target using groundbreaking approach

Scientists determine structure of important drug target using groundbreaking approach

Tempe, Arizona (July 23, 2015)-Using the brightest X-ray laser in the world, scientists have determined the structure of a molecular complex that is responsible for our sense of sight.

Researchers at Arizona State University's Biodesign Institute Center for Applied Structural Discovery (CASD) collaborated with an international team of researchers from 19 institutions working to develop a roadmap for more selectively targeting pathways for drug treatment. The innovative approach may lead to more effective therapies with fewer side effects, particularly 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 in the journal Nature.

The new research focuses on a signaling protein called arrestin, which plays a vital role in cellular communication, and a G protein-coupled receptor (GPCR) called rhodopsin, which is instrumental in our sense of sight.

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.

"Arrestin and G proteins are the yin and the yang of regulating GPCR function," said H. Eric Xu, Ph.D., from Van Andel Research Institute (VARI), Grand Rapids, MI who led the study. "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."

Researchers at CASD helped to pioneer a new technique called femtosecond crystallography, which takes advantage of a cutting edge X-ray Free Electron Laser (XFEL) instrument at the Department of Energy's (DOE) SLAC National Accelerator Laboratory, Stanford. The instrument can generate X-ray pulses that are a billion times brighter than previous X-ray sources, and that are so short that the biomolecule structure is imaged before it is destroyed. 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. (Femtosecond X-ray pulses are almost unfathomably brief. The time difference between one femtosecond and a second is the same as the difference between a second and 32 million years!)

"This is an important step forward in understanding how human vision works at the molecular level, and a dramatic demonstration of the power of the X-ray laser at the SLAC DOE National Laboratory to reveal new molecular structures and their function," said John Spence, Regents' Professor of physics, Scientific Director for the National Science Foundation's BioXFEL Science and Technology Center and member of the CASD research team.

Contributions from ASU researchers included crystallization and biophysical characterization of the rhodopsin-arrestin constructs and crystals, X-ray data collection and evaluation, as well as development of the devices that deliver the stream of nanocrystals.

The work is based on a team effort of ASU faculty, Wei Liu, Petra Fromme, Raimund Fromme John Spence, and Uwe Weierstall with their teams of researchers and students including: researchers Nadia Zatsepin and Stella Lisova from the Department of Physics as well as the graduate students Shibom Basu, Jesse Coe, Chelsie Conrad and Shatabdi Roy-Chowdhury from the School of Molecular Sciences, and Daniel James and Dingjie Wang from the Department of Physics.

In the future, the researchers hope to study the signaling protein arrestin with other GPCRs that are involved in heart disease and cancer as well as to use this structure to screen for drug compounds that are designed to treat these diseases with far fewer side effects, which will have a dramatic impact on human health.

"There are a number of other GPCRs that are critical to many of the processes in our bodies, like seeing, touching, hearing, smelling, tasting and feeling pain, and when they become dysfunctional it can lead to devastating diseases such as cancer" said Wei Liu, Assistant Professor in the School of Molecular Sciences and member of CASD. "This study provides important clues about how we can improve human health and make important progress in the fight against cancer and other incurable human diseases."

Contact: Richard Harth richard.harth@asu.edu 480-727-0378