Signaling Sighted | Chemical & Engineering News

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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).

Credit: Nature

This computer generated model is a result of X-ray crystalography showing a G protien with its receptor stablilized by a llama antibody.

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).

Credit: Nature

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Comparison of a portion of a G protein bound (solid) and not bound (gray shadow) to its GPCR. Pink and red sections exhibit the greatest movement according to mass spectrometry analysis. Guanosine diphosphate is represented as a space-filling model.

Credit: Courtesy of Roger K. Sunahara

This structure shows a G protein bound to a coupling receptor and a G protein not bonud to a coupling receptor.

Comparison of a portion of a G protein bound (solid) and not bound (gray shadow) to its GPCR. Pink and red sections exhibit the greatest movement according to mass spectrometry analysis. Guanosine diphosphate is represented as a space-filling model.

Credit: Courtesy of Roger K. Sunahara

For the first time, researchers this year obtained an atomic-resolution crystal structure of a G protein-coupled receptor (GPCR) together with its G protein partner (C&EN, Aug. 1, page 9; Nature, DOI: 10.1038/nature10361). Given the central role of GPCRs in molecular signaling, the new view showing how a receptor activates a G protein has implications for both fundamental biochemistry and drug design. Stanford University’s Brian K. Kobilka and the University of Michigan’s Roger K. Sunahara led the effort to solve the X-ray structure of the β₂ adrenergic receptor with its G protein. They harnessed antibodies from llamas, tailored a crystallization matrix for the membrane proteins, and used specialized detergents to keep the complex stable. With the structure in hand, “instead of targeting drugs to the extracellular surface of the receptor, it may be possible to target drugs to the receptor-G protein interface,” said Christopher G. Tate, a crystallographer at England’s MRC Laboratory of Molecular Biology. The researchers also used electron microscopy (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas.1113645108) and hydrogen-deuterium exchange mass spectrometry (Nature, DOI: 10.1038/nature10488) to examine the interaction (C&EN, Oct. 3, page 34). Taken together, the team’s results suggest the receptor kicks off signaling by engaging the N-terminus of the G protein, tugging on it, and interfering with the region of the G protein that binds the β phosphate of the nucleoside guanosine diphosphate, triggering its release, Sunahara said.