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Originally published in Science Express on 25 October 2007
Science 23 November 2007:
Vol. 318. no. 5854, pp. 1258 - 1265
DOI: 10.1126/science.1150577
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Research Articles

High-Resolution Crystal Structure of an Engineered Human β2-Adrenergic G Protein–Coupled Receptor

Vadim Cherezov,1* Daniel M. Rosenbaum,2* Michael A. Hanson,1 Søren G. F. Rasmussen,2 Foon Sun Thian,2 Tong Sun Kobilka,2 Hee-Jung Choi,2,3 Peter Kuhn,4 William I. Weis,2,3 Brian K. Kobilka,2{dagger} Raymond C. Stevens1{dagger}

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.

1 Department of Molecular Biology, Scripps Research Institute, La Jolla, CA 92037, USA.
2 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
3 Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
4 Department of Cell Biology, Scripps Research Institute, La Jolla, CA 92037, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: stevens{at}scripps.edu (R.C.S.); kobilka{at}stanford.edu (B.K.K.)

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