SIGHTING SIGNALING BIOCHEMISTRY: Collaboration
enables the first view of a receptor with its G protein
OR THE FIRST TIME, researchers have obtained an atomic-resolution image of a G-proteincoupled receptor (GPCR) together with its G protein partner (Nature, DOI: 10.1038/nature10361). The structure, solved with help from a battery of protein stabilization techniques, has implications for both fundamental biochemistry and drug design. “This structure shows for the first time how a receptor activates a G protein, which is a cornerstone of receptor biology,” says Christopher G. Tate, an expert in GPCR crystallography at the Medical Research Council Laboratory of Molecular Biology, in England, who was not involved in the research. “This is a huge advance in the field and something people have been awaiting for years.” GPCRs straddle cell membranes, snaking back and forth seven times, and activate associated G proteins inside the cell. The system transmits signals from hormones, odors, or light from the outside of the cell to the inside. The receptors are targets of as many as 40% of drugs on the market. A handful of GPCR structures have debuted (C&EN, March 14, page 15). But a picture of a fully active GPCR with its G protein had eluded scientists. Now, Stanford University GPCR expert Brian K. Kobilka and University of Michigan, Ann Arbor, G protein biochemist Roger K. Sunahara have marshaled the expertise of more than a half-dozen research teams to reach that goal. The group solved the structure of a GPCR called the β2 adrenergic receptor with its G protein, aided by technologies such as antibodies from llamas (C&EN, May 2, page 40), modifications to a crystal-
F
lization matrix for membrane proteins called the lipidic cubic phase, and specialized detergents for keeping the delicate protein complex stable (C&EN, Nov. 8, 2010, page 12). “We have a lot of great collaborators,” Kobilka says. “They realized this was a difficult problem, and they were willing to try things that might fail.” “We had just a small part in the extraordinary experimental process that led Kobilka and his colleagues to the final structure,” says Samuel H. Gellman of the University of Wisconsin, Madison, who with former postdoc Pil Seok Chae provided the detergents. “We were proud to enable molecular design and organic synthesis to play a supporting role in this saga.” The structure itself holds a few surprises, Sunahara says. For instance, the G protein opens wider than expected to release guanosine diphosphate, a crucial part of the G protein activation process. Tate, cofounder of biopharmaceutical company Heptares Therapeutics, says the structure has implications for drug design. “One possibility is that instead of targeting drugs to the extracellular surface of the receptor, it may be possible to target drugs to the receptor-G protein interface,” he explains. The structure’s success is allowing some researchers on Kobilka’s team to begin long-deferred professional plans. Chae, who now works in industry in his native South Korea, turned down two job offers and extended his time in Madison to finish the detergent collaborations. And Kobilka postdoc Søren G. F. Rasmussen has put off starting a lab of his own at the University of Copenhagen’s Panum Institute until November. Part of the reason is that the labs are being remodeled, Rasmussen says. “But I wasn’t rushing to get back because I wanted to finish this project.”—
NATURE
NEWS OF THE WEEK
An X-ray crystal structure depicts the β2 adrenergic receptor (green) with its G protein, a heterotrimer called Gs (yellow, blue, purple). The complex is stabilized by a llama antibody (red) and the enzyme T4 lysozyme (magenta).
CARMEN DRAHL
STEM CELLS NIH welcomes dismissal of lawsuit that would stop funding of research A federal judge has thrown out a case that in August 2010 briefly shut down government-funded research on human embryonic stem cells and threatened to stop the work altogether. The ruling clears the way for the National Institutes of Health to continue funding the controversial research. Two scientists filed the lawsuit against NIH, claiming that the agency’s policy violates the Dickey-Wicker Amendment, a law that prohibits federal funding of any research that destroys human embryos. NIH countered that it funds research involving
previously derived embryonic stem cells. Chief Judge Royce C. Lamberth of the U.S. District Court for the District of Columbia ruled last August that the plaintiffs’ argument had merit and issued a preliminary injunction ordering NIH to stop funding human embryonic stem cell research. But a federal appeals court lifted the injunction in April, ruling that the law “does not extend to past actions” (C&EN, May 9, page 12). Saying his hands were tied by the appellate court’s decision, Lamberth dismissed the lawsuit on July 27.
WWW.CEN-ONLINE.ORG
9
AUGUST 1 , 20 11
Biomedical researchers and NIH officials were overjoyed by the lawsuit’s dismissal, saying it will allow groundbreaking research that could lead to cures and treatments for numerous diseases. The litigation, however, is likely to continue. The plaintiffs plan to review all options for an appeal, according to their attorney, Steven H. Aden of the Alliance Defense Fund. “In these tough economic times, it makes no sense for the federal government to use taxpayer money for this illegal and unethical purpose,” Aden says.—BRITT ERICKSON
