Article

Nature 450, 383-387 (15 November 2007) | doi:10.1038/nature06325; Received 26 July 2007; Accepted 28 September 2007; Published online 21 October 2007

Crystal structure of the human bold beta2 adrenergic G-protein-coupled receptor

Søren G. F. Rasmussen1,6, Hee-Jung Choi1,2,6, Daniel M. Rosenbaum1,6, Tong Sun Kobilka1, Foon Sun Thian1, Patricia C. Edwards3, Manfred Burghammer4, Venkata R. P. Ratnala1, Ruslan Sanishvili5, Robert F. Fischetti5, Gebhard F. X. Schertler3, William I. Weis1,2 & Brian K. Kobilka1

  1. Department of Molecular and Cellular Physiology and,
  2. Department of Structural Biology, Stanford University School of Medicine, 279 Campus Drive, Stanford, Palo Alto, California 94305, USA
  3. MRC Laboratory of Molecular Biology, Cambridge CB2 2QH, UK
  4. European Synchrotron Radiation Facility, 6 rue Jules Horowitz, BP220, 38043 Grenoble, cedex 9, France
  5. Biosciences Division, Argonne National Laboratory, GM/CA-CAT, Boulevard 436, D007, 9700 South Cass Avenue, Argonne, Illinois 60439, USA
  6. These authors contributed equally to this work.

Correspondence to: Brian K. Kobilka1 Correspondence and requests for materials should be addressed to B.K.K. (Email: kobilka@stanford.edu).

Top

Structural analysis of G-protein-coupled receptors (GPCRs) for hormones and neurotransmitters has been hindered by their low natural abundance, inherent structural flexibility, and instability in detergent solutions. Here we report a structure of the human beta2 adrenoceptor (beta2AR), which was crystallized in a lipid environment when bound to an inverse agonist and in complex with a Fab that binds to the third intracellular loop. Diffraction data were obtained by high-brilliance microcrystallography and the structure determined at 3.4 Å/3.7 Å resolution. The cytoplasmic ends of the beta2AR transmembrane segments and the connecting loops are well resolved, whereas the extracellular regions of the beta2AR are not seen. The beta2AR structure differs from rhodopsin in having weaker interactions between the cytoplasmic ends of transmembrane (TM)3 and TM6, involving the conserved E/DRY sequences. These differences may be responsible for the relatively high basal activity and structural instability of the beta2AR, and contribute to the challenges in obtaining diffraction-quality crystals of non-rhodopsin GPCRs.

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