For the first time, researchers have obtained an atomic-resolution image of a G-protein-coupled 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 crystallization 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.”