TY - JOUR
T1 - Crystal structure of the human β2 adrenergic G-protein-coupled receptor
AU - Rasmussen, Søren G F
AU - Choi, Hee Jung
AU - Rosenbaum, Daniel M.
AU - Kobilka, Tong Sun
AU - Thian, Foon Sun
AU - Edwards, Patricia C.
AU - Burghammer, Manfred
AU - Ratnala, Venkata R P
AU - Sanishvili, Ruslan
AU - Fischetti, Robert F.
AU - Schertler, Gebhard F X
AU - Weis, William I.
AU - Kobilka, Brian K.
N1 - Funding Information:
Acknowledgements This study was supported by the Lundbeck Foundation (S.G.F.R.), a National Institutes of Health Ruth L. Kirchstein NRSA grant (D.M.R.), a National Institute of General Medical Sciences grant (W.I.W.), a National Institute of Neurological Disorders and Stroke grant, the Mather Charitable Foundation, and a generous gift from Lundbeck (to B.K.K). G.F.X.S. was financially supported by a Human Frontier Science Project (HFSP) programme grant, a European Commission FP6 specific targeted research project and an ESRF long-term proposal. We thank R. Mackinnon and J. Bowie for advice, R. Stevens for help with early screening efforts, and J. Smith for arranging access to GM/CA-CAT at the APS. Use of the APS is supported by the US Department of Energy. GM/CA-CAT is funded by the US National Institutes of Cancer and General Medical Sciences. We thank X. Deupi and S. Granier for help with data collection. We thank D. Flot for his support at the ID 23.2 microfocus beamline at the European Synchrotron Radiation Facility.
PY - 2007/11/15
Y1 - 2007/11/15
N2 - 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 β2 adrenoceptor (β2AR), 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 β2AR transmembrane segments and the connecting loops are well resolved, whereas the extracellular regions of the β2AR are not seen. The β2AR 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 β2AR, and contribute to the challenges in obtaining diffraction-quality crystals of non-rhodopsin GPCRs.
AB - 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 β2 adrenoceptor (β2AR), 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 β2AR transmembrane segments and the connecting loops are well resolved, whereas the extracellular regions of the β2AR are not seen. The β2AR 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 β2AR, and contribute to the challenges in obtaining diffraction-quality crystals of non-rhodopsin GPCRs.
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U2 - 10.1038/nature06325
DO - 10.1038/nature06325
M3 - Article
C2 - 17952055
AN - SCOPUS:36248970132
SN - 0028-0836
VL - 450
SP - 383
EP - 387
JO - Nature
JF - Nature
IS - 7168
ER -