Editors' ChoiceStructural Biology

β2-Adrenergic Receptor Structures

STKE  27 Nov 2007:
Vol. 2007, Issue 414, pp. tw434
DOI: 10.1126/stke.4142007tw434

Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) are transmembrane proteins that respond to diverse extracellular stimuli to trigger many different cellular responses. They are important pharmacological targets, but drug design has been hampered because structural information is only available for the rather distinctive member of this family, rhodopsin (see the Perspective by Ranganathan). Three studies now provide structural insights into another GPCR, the human β2-adrenergic receptor. All three groups crystallized the protein in the presence of an inverse agonist that stabilizes the inactive conformation of the receptor. Rosenbaum et al. stabilized the protein for crystallization by protein engineering and analyzed mutagenesis data in the context of the structure to provide insight into how ligand binding is coupled. Cherezov et al. describe in detail the 2.4 Å structure of the fusion protein and how it compares to the rhodopsin structure. Rasmussen et al. crystallized the protein in a lipid environment in the presence of a monoclonal antibody fragment to obtain a 3.4 Å structure. It appears that conserved helices provide a common core in class A GPCRs, whereas variable helices provide binding-site plasticity.

V. Cherezov, D. M. Rosenbaum, M. A. Hanson, S. G. F. Rasmussen, F. S. Thian, T. S. Kobilka, H.-J. Choi, P. Kuhn, W. I. Weis, B. K. Kobilka, R. C. Stevens, High-resolution crystal structure of an engineered human β2-adrenergic G protein-coupled receptor. Science 318, 1258-1265 (2007). [Abstract] [Full Text]

D. M. Rosenbaum, V. Cherezov, M. A. Hanson, S. G. F. Rasmussen, F. S. Thian, T. S. Kobilka, H.-J. Choi, X.-J. Yao, W. I. Weis, R. C. Stevens, B. K. Kobilka, GPCR engineering yields high-resolution structural insights into β2-adrenergic receptor function. Science 318, 1266-1273 (2007). [Abstract] [Full Text]

S. G. F. Rasmussen, H.-J. Choi, D. M. Rosenbaum, T. S. Kobilka, F. S. Thian, P. C. Edwards, M. Burghammer, V. R. P. Ratnala, R. Sanishvili, R. F. Fischetti, G. F. X. Schertler, W. I. Weis, B. K. Kobilka, Crystal structure of the human β2 adrenergic G-protein-coupled receptor. Nature 450, 383-387 (2007). [PubMed]

R. Ranganathan, Signaling across the cell membrane. Science 318, 1253-1254 (2007). [Abstract] [Full Text]