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

Research output: Contribution to journalArticle

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Abstract

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
JournalScience
Volume318
Issue number5854
DOIs
StatePublished - Nov 23 2007

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Adrenergic Agents
Rhodopsin
G-Protein-Coupled Receptors
Ligands
Adrenergic Receptors
Binding Sites
Guanine Nucleotides
Muramidase
Crystallization
Disulfides
Signal Transduction
Carrier Proteins
Proteins
Cholesterol
Membranes
human CCR10 protein
carazolol

ASJC Scopus subject areas

  • General

Cite this

Cherezov, V., Rosenbaum, D. M., Hanson, M. A., Rasmussen, S. G. F., Foon, S. T., Kobilka, T. S., ... 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

High-resolution crystal structure of an engineered human β2-adrenergic G protein-coupled receptor. / Cherezov, Vadim; Rosenbaum, Daniel M.; Hanson, Michael A.; Rasmussen, Søren G F; Foon, Sun Thian; Kobilka, Tong Sun; Choi, Hee Jung; Kuhn, Peter; Weis, William I.; Kobilka, Brian K.; Stevens, Raymond C.

In: Science, Vol. 318, No. 5854, 23.11.2007, p. 1258-1265.

Research output: Contribution to journalArticle

Cherezov, V, Rosenbaum, DM, Hanson, MA, Rasmussen, SGF, Foon, ST, Kobilka, TS, Choi, HJ, Kuhn, P, Weis, WI, Kobilka, BK & Stevens, RC 2007, 'High-resolution crystal structure of an engineered human β2-adrenergic G protein-coupled receptor', Science, vol. 318, no. 5854, pp. 1258-1265. https://doi.org/10.1126/science.1150577
Cherezov, Vadim ; Rosenbaum, Daniel M. ; Hanson, Michael A. ; Rasmussen, Søren G F ; Foon, Sun Thian ; Kobilka, Tong Sun ; Choi, Hee Jung ; Kuhn, Peter ; Weis, William I. ; Kobilka, Brian K. ; Stevens, Raymond C. / High-resolution crystal structure of an engineered human β2-adrenergic G protein-coupled receptor. In: Science. 2007 ; Vol. 318, No. 5854. pp. 1258-1265.
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