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
Raymond C. Stevens1
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.
To whom correspondence should be addressed. E-mail: stevens{at}scripps.edu (R.C.S.); kobilka{at}stanford.edu (B.K.K.)
