Crystal structure of the human beta sub(2) adrenergic G-protein-coupled receptor

• Published in: Nature 2007-11, Vol.450 (7168), p.383-387
• Main Authors: Rasmussen, Soeren GF, Choi, Hee-Jung, Rosenbaum, Daniel M, Kobilka, Tong Sun, Thian, Foon Sun, Edwards, Patricia C, Burghammer, Manfred, Ratnala, Venkata RP, Sanishvili, Ruslan, Fischetti, Robert F, Schertler, Gebhard FX, Weis, William I, Kobilka, Brian K
• Format: Article
• Language: English
• ISSN: 0028-0836; 1476-4679
• DOI: 10.1038/nature06325

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 beta sub(2) adrenoceptor (beta sub(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 Aa/3.7 Aa resolution. The cytoplasmic ends of the beta sub(2)AR transmembrane segments and the connecting loops are well resolved, whereas the extracellular regions of the beta sub(2)AR are not seen. The beta sub(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 beta sub(2)AR, and contribute to the challenges in obtaining diffraction- quality crystals of non-rhodopsin GPCRs.