G-protein-coupled receptors, or GPCRs, are a large family of proteins embedded in a cell’s membrane that sense molecules outside the cell and activate a cascade of different cellular processes in response. They constitute key components of how cells interact with their environments and are the target of nearly half of today’s pharmaceuticals.
These medicines work by connecting with many of the 800 or so human GPCRs. But to do this well, a drug needs to connect to the protein like a key opens a lock. Improving drugs requires knowing exactly how these proteins work and are structured, which is difficult because the long, slender protein chains are folded in an intricate pattern that threads in and out of the cell’s membrane.
In a study performed at Argonne in 2007, Kobilka, a professor at Stanford University, and his colleagues used intense x-rays from the Laboratory’s Advanced Photon Source (APS) to make the first discovery of the structure of a human GPCR. This receptor, called the human β2 adrenoreceptor (β2AR), is responsible for a number of different biological responses, including facilitating breathing and dilating the arteries.
A second and potentially even more exciting breakthrough occurred in 2011, when the Kobilka group used the APS to determine the structure of β2AR at the exact moment that the protein-receptor complex signals across the membrane. This study represented the first time that a GPCR had been caught “in the act” of carrying out its biological mission.
"It is especially gratifying that Dr. Kobilka and his fellow researchers used the Advanced Photon Source at the Department of Energy’s Argonne National Lab to reveal a high-resolution structure of a cell receptor in the act of signaling," said Secretary of Energy Steven Chu. "In the past decade, work done at Department of Energy Laboratories has been recognized with four Chemistry and three Physics Nobel Prizes. The foundation of this world-class science has been the result of long-term, stable federal government investments."
“By understanding more about the ways these cellular receptors function, we can open new frontiers in biology and develop more effective drug therapies for serious illnesses,” said Argonne Director Eric D. Isaacs. “This Nobel Prize recognizes these scientists’ great research and highlights the National Laboratories’ vital contributions to scientific discovery.”
In order to obtain the structure of a GPCR, Kobilka and his colleagues turned to x-ray crystallography, a process that can locate each of the atoms within a larger molecule such as a GPCR. “The combination of intense x-rays and cutting-edge crystallography capabilities at the APS gave the researchers an outstanding tool tailored especially for this kind of experiment,” said APS Associate Laboratory Director Brian Stephenson. “There are very few research facilities where these breakthroughs could have been made.”
“Argonne leads the world when it comes to developing and providing access to new crystallographic instruments and techniques,” Kobilka said last year.
Some of the earliest studies of GPCR structures were performed at the European Synchrotron Radiation Facility in France, but Kobilka and his team subsequently moved their experiments to Argonne. “We had an x-ray beam that was stable enough, intense enough, and could be focused to a small enough spot so that Kobilka could get a good view of the structure,” said University of Michigan crystallographer Janet Smith, who is Scientific Director of the GM/CA beamline 23-ID where Kobilka did his work at the APS.
Part of what attracted Kobilka to Argonne was the development of a device known as a “minibeam collimator,” which helped crystallographers focus their beams even more tightly. “The great thing about this experiment is that the importance of the result drove the technology forward,” said X-ray Science Division Associate Division Director and GM/CA Group Leader Robert Fischetti. “Once they were able to solve the first structure, the floodgates really opened.”
More recent Kobilka research that used APS x-rays to study GPCRs examined the structure of receptors that bind to opioids, the class of molecules including heroin and oxycodone and implicated in some of the brain’s most powerful addictive pathways. In all, to date he has been a coauthor on 11 papers with an Argonne connection.
Søren G. F. Rasmussen2, Brian T. DeVree, Yaozhong Zou, Andrew C. Kruse, Ka Young Chung, Tong Sun Kobilka, Foon Sun Thian, Pil Seok Chae, Els Pardon, Diane Calinski, Jesper M.Mathiesen, Syed T. A. Shah, Joseph A. Lyons, Martin Caffrey, Samuel H. Gellman, Jan Steyaert,Georgios Skiniotis,William I. Weis, Roger K.Sunahara, and Brian K. Kobilka, “Crystal structure of the b2 adrenergic receptor–Gs protein complex,”Natrue 447, 549 (29 September 2011). D0I:10.1038/nature10361.
Søren G. F. Rasmussen, Hee-Jung Choi, Daniel M. Rosenbaum, Tong Sun Kobilka, Foon Sun Thian, Patricia C. Edwards, Manfred Burghammer, Venkata R. P. Ratnala, Ruslan Sanishvili, Robert F. Fischetti, Gebhard F. X. Schertler, William I. Weis &Brian K. Kobilka, “Crystal structure of the human beta2 adrenergic G-protein-coupled receptor,” Nature 450, 383 (15 November 2007) DOI:10.1038/nature06325.
Daniel M. Rosenbaum, Vadim Cherezov, Michael A. Hanson, Søren G. F. Rasmussen, Foon Sun Thian, Tong Sun Kobilka, Hee-Jung Choi, Xiao-Jie Yao, William I. Weis, Raymond C. Stevens, and Brian K. Kobilka, “GPCR Engineering Yields High-Resolution Structural Insights into β2-Adrenergic Receptor Function,” doi: 10.1126/science.1150609.Science 318, 1266 (23 November 2007).
Use of the Advanced Photon Source at Argonne National Laboratory was supported by the DOE’s Office of Science under Contract No. DE-AC02-06CH11357.
The Advanced Photon Source at Argonne National Laboratory is one of five national synchrotron radiation light sources supported by the U.S. Department of Energy’s Office of Science to carry out applied and basic research to understand, predict, and ultimately control matter and energy at the electronic, atomic, and molecular levels, provide the foundations for new energy technologies, and support DOE missions in energy, environment, and national security. To learn more about the Office of Science x-ray user facilities, visit http://science.energy.gov/user-facilities/basic-energy-sciences/.
Argonne National Laboratory seeks solutions to pressing national problems in science and technology. The nation's first national laboratory, Argonne conducts leading-edge basic and applied scientific research in virtually every scientific discipline. Argonne researchers work closely with researchers from hundreds of companies, universities, and federal, state and municipal agencies to help them solve their specific problems, advance America's scientific leadership and prepare the nation for a better future. With employees from more than 60 nations, Argonne is managed by UChicago Argonne, LLC for the U.S. Department of Energy's Office of Science.