GPCR-G-Protein Complex

Drug discovery stands to benefit from structure of membrane protein with its signaling partner

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It’s the most squirm-inducing scene in “Pulp Fiction”: Panicked hit man John Travolta must revive mob wife Uma Thurman from a heroin overdose. So he plunges a syringe loaded with adrenaline into her heart. The film premiered in 1994. At the time, scientists lacked a precise picture of how the century-old drug worked.

The picture is clearer today, thanks to the 2011 X-ray crystal structure of adrenaline’s target, the β2 adrenergic receptor, together with the receptor’s signaling partner (Nature, DOI: 10.1038/nature10361; C&EN, Aug. 1, 2011, page 9). This receptor is one of a large family of proteins called G protein-coupled receptors (GPCRs). These proteins crisscross the cell membrane seven times, transmitting messages from hormones, neurotransmitters, and even light. They are targets for as many as 50% of drugs on the market.

The first X-ray crystal structure of a GPCR appeared in 2000, with many more beginning in 2007. But without a G protein partner in the structure, researchers were only part of the way to seeing how signals from outside the cell get transmitted inside. The 2011 work suggests that the receptor functions by engaging the C-terminus of the G protein, tugging on it, and interfering with the region of the G protein that binds an important intracellular messenger—the nucleoside guanosine diphosphate.

Stanford University’s Brian K. Kobilka, who led the structure quest, shared the 2012 Nobel Prize in Chemistry. He says that GPCR structures in general and this structure in particular could not have been obtained without technological advances from many labs. These include stabilizing accessory proteins, a membrane-mimicking medium called the lipidic cubic phase, and new types of amphiphilic detergents. Another boost came from powerful yet highly focused X-ray beam lines. These allow researchers to collect useful data from GPCR crystals, which tend to be smaller than other proteins’.


For many years, researchers only had GPCR cartoons like this one to go on.
Nobel Foundation

Nobody has solved another GPCR-G protein structure. “We absolutely need more,” Kobilka says. The structure represents one snapshot in a dynamic process, he adds.

And drugmakers want to see how these kinds of structures can inspire new medicines that can direct GPCRs to couple to different signaling pathways, adds Fiona Marshall, chief scientific officer of Heptares Therapeutics, a GPCR-targeted pharmaceutical company.

“I think it’s too early to say what this structure means in terms of fundamental approaches to drug discovery,” Kobilka says. “We’re working hard to get other ones.”

I watched “Pulp Fiction” in college, at about the same time I first saw a picture of a GPCR. It was a cartoon. Back then, researchers had no GPCR crystal structures. That so much has changed in my short lifetime reassures me of how much is still left to discover.—Carmen Drahl


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