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

2510 Scopus citations

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

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'High-resolution crystal structure of an engineered human β<sub>2</sub>-adrenergic G protein-coupled receptor'. Together they form a unique fingerprint.

  • Cite this

    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