Journal Article

Crystal structure of the human β2 adrenergic G-protein-coupled receptor

Burghammer, Manfred, Rasmussen, Søren G. F., Thian, Foon Sun, Schertler, Gebhard F. X., Rosenbaum, Daniel M., Ratnala, Venkata R. P., Choi, Hee-Jung, Fischetti, Robert F., Sanishvili, Ruslan, Kobilka, Tong Sun, Kobilka, Brian K., Edwards, Patricia C., Weis, William I.

2007

Overview

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 β 2 adrenoceptor (β 2 AR), 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 β 2 AR transmembrane segments and the connecting loops are well resolved, whereas the extracellular regions of the β 2 AR are not seen. The β 2 AR 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 β 2 AR, and contribute to the challenges in obtaining diffraction-quality crystals of non-rhodopsin GPCRs. A tough structure to crack Most hormones and neurotransmitters — and therefore many drugs — work via G protein-coupled receptors, or GPCRs. With the one exception of rhodopsin, the most stable GPCR known, structural data for these proteins are hard to come by. Now several collaborating research groups, publishing in this issue of Nature and also in Science , have exploited a raft of different techniques, including the use of the inverse agonist carazolol to stabilize the receptor structure, to determine the crystal structure of the human β 2 AR adrenaline receptor. Its structure contrasts markedly with that of 'dark' rhodopsin, which helps explain why it is so hard to prepare diffraction-quality crystals of most GPCRs. High resolution structural information for G protein-coupled receptors has so far been limited to rhodopsin; here a crystal structure of the β 2 AR adrenaline receptor is presented.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: Biological and medical sciences / Crystalline structure / Fundamental and applied biological sciences. Psychology / Humanities and Social Sciences / Molecular biophysics / multidisciplinary / Science / Structure in molecular biology