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Structural Studies of the Β2-Adrenergic Receptor Gs Complex

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Structural Studies of the Β2-Adrenergic Receptor Gs Complex Structural Studies of the β2-Adrenergic Receptor Gs Complex Gerwin Westfield,1,2 Soren Rasmussen,3 Min Su,1 Brian Kobilka,3 and Georgios Skiniotis 1,2 1 Life Sciences Institute, University of Michigan, 210 Washtenaw Ave., Ann Arbor, MI 48109-2216 2 Department of Biological Chemistry, University of Michigan, 210 Washtenaw Ave., Ann Arbor, MI 48109-2216 3 Department of Molecular and Cellular Physiology and Medicine, Stanford University, 279 Campus Drive, Stanford, CA 94305-5345 G-protein-coupled receptors (GPCRs) are seven-helix transmembrane proteins responsible for integrating extracellular stimuli to an intracellular response [1]. When an extracellular ligand binds to the receptor, a conformational change occurs that is transmitted to the intracellularly bound G- protein trimer. G-proteins regulate many cellular functions including metabolic enzymes, ion channels, and transporters. Due to their central role in physiological responses, GPCRs constitute ~30% of all prescription drug targets. Determining the structure of these important receptors in complex with their coupled G-protein will help to understand how they regulate cellular signals, as well as help to create new therapeutics for the treatment of several diseases. Despite the fact that several crystal structures of G-proteins and GPCRs have been solved independently [2], and the structure of these proteins together in a complex has defied researchers for the last 50 years [3]. In collaboration with the lab of Brian Kobilka we are trying to resolve the architecture of a GPCR-G- protein complex with the application of single-particle EM. The β2-adrenergic receptor Gs complex (β2AR-Gs) is approximately 140 kDa, consisting of the transmembrane receptor and the G-protein heterotrimer of Gsα and βγ. We have imaged the complex embedded in negative stain (see Figure 1) and produced a first 3D model generated by random conical tilt (RCT) approach (Figure 2A). Subsequently, we generated a 3D reconstruction of the complex from cryo-EM data, using the negative stain 3D model as an initial reference. (Figure 2B) Based on the docking of the crystal structures of the transmembrane receptor and G- protein heterotrimer in the EM envelopes, we have produced a first EM model for the architecture of this physiologically important signaling complex. References: 1. Gether, U. and Kobilka, B.K. G Protein-coupled Receptors: Mechanism of Agonist activation. J. Biol. Chem. 1997. 273: p. 17979-82. 2. Rasmussen, S.G.F, Choi, H.J, Rosenbaum, D.M., Kobilka, T.S., Thian, F.S., Edwards, P.C., Burghammer, M., Rratnala, V.R.P, Sanishvili, R. Fischetti, R.F., Schertler, G.F.X, Weis, W.I., Kobilka, B.K ., Crystal structure of the human beta 2 adrenergic G protein coupled receptor. Nature, 2007. 450:383-7. 3. Rosenbaum, D.M., Rasmussen, S.G., Kobilka, B.K. The structure and function of G-protein- coupled receptors. Nature, 2009. 459(7245): 356-363 Figure 1. Raw negative stain micrograph of the β2AR-Gs complex. Figure 2. (A) 3D reconstruction of β2AR-Gs complex from negative stain images using random conical tilt. (B) 3D reconstruction of β2AR-Gs complex from cryo-EM. Cryo-EM map has the crystal structures of transmembrane receptor and G-protein heterotrimer docked within the 3D envelope. .
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