High-resolution crystal structure of an engineered human β2-adrenergic G protein-coupled receptor

Vadim Cherezov, Daniel M. Rosenbaum, Michael A. Hanson, Søren G F Rasmussen, Sun Thian Foon, Tong Sun Kobilka, Hee Jung Choi, Peter Kuhn, William I. Weis, Brian K. Kobilka, Raymond C. Stevens

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Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors constitute the largest family of eukaryotic signal transduction proteins that communicate across the membrane. We report the crystal structure of a human β2-adrenergic receptor-T4 lysozyme fusion protein bound to the partial inverse agonist carazolol at 2.4 angstrom resolution. The structure provides a high-resolution view of a human G protein-coupled receptor bound to a diffusible ligand. Ligand-binding site accessibility is enabled by the second extracellular loop, which is held out of the binding cavity by a pair of closely spaced disulfide bridges and a short helical segment within the loop. Cholesterol, a necessary component for crystallization, mediates an intriguing parallel association of receptor molecules in the crystal lattice. Although the location of carazolol in the β2-adrenergic receptor is very similar to that of retinal in rhodopsin, structural differences in the ligand-binding site and other regions highlight the challenges in using rhodopsin as a template model for this large receptor family.

Original languageEnglish (US)
Pages (from-to)1258-1265
Number of pages8
Issue number5854
StatePublished - Nov 23 2007

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    Cherezov, V., Rosenbaum, D. M., Hanson, M. A., Rasmussen, S. G. F., Foon, S. T., Kobilka, T. S., Choi, H. J., Kuhn, P., Weis, W. I., Kobilka, B. K., & Stevens, R. C. (2007). High-resolution crystal structure of an engineered human β2-adrenergic G protein-coupled receptor. Science, 318(5854), 1258-1265. https://doi.org/10.1126/science.1150577