TY - GEN
T1 - Crystal structures of the β2-adrenergic receptor
AU - Weis, William I.
AU - Rosenbaum, Daniel M.
AU - Rasmussen, Søren G F
AU - Choi, Hee Jung
AU - Thian, Foon Sun
AU - Kobilka, Tong Sun
AU - Yao, Xiao Jie
AU - Day, Peter W.
AU - Parnot, Charles
AU - Fung, Juan J.
AU - Ratnala, Venkata R P
AU - Kobilka, Brian K.
AU - Cherezov, Vadim
AU - Hanson, Michael A.
AU - Kuhn, Peter
AU - Stevens, Raymond C.
AU - Edwards, Patricia C.
AU - Schertler, Gebhard F X
AU - Burghammer, Manfred
AU - Sanishvili, Ruslan
AU - Fischetti, Robert F.
AU - Masood, Asna
AU - Rohrer, Daniel K.
PY - 2009/12/1
Y1 - 2009/12/1
N2 - G protein coupled receptors (GPCRs) constitute the largest family of membrane proteins in the human genome, and are responsible for the majority of signal transduction events involving hormones and neurotransmitters across the cell membrane. GPCRs that bind to diffusible ligands have low natural abundance, are relatively unstable in detergents, and display basal G protein activation even in the absence of ligands. To overcome these problems two approaches were taken to obtain crystal structures of the β2-adrenergic receptor (β2AR), a well-characterized GPCR that binds catecholamine hormones. The receptor was bound to the partial inverse agonist carazolol and co-crystallized with a Fab made to a three-dimensional epitope formed by the third intracellular loop (ICL3), or by replacement of ICL3 with T4 lysozyme. Small crystals were obtained in lipid bicelles (β2AR-Fab) or lipidic cubic phase (β2AR-T4 lysozyme), and diffraction data were obtained using microfocus technology. The structures provide insights into the basal activity of the receptor, the structural features that enable binding of diffusible ligands, and the coupling between ligand binding and G-protein activation.
AB - G protein coupled receptors (GPCRs) constitute the largest family of membrane proteins in the human genome, and are responsible for the majority of signal transduction events involving hormones and neurotransmitters across the cell membrane. GPCRs that bind to diffusible ligands have low natural abundance, are relatively unstable in detergents, and display basal G protein activation even in the absence of ligands. To overcome these problems two approaches were taken to obtain crystal structures of the β2-adrenergic receptor (β2AR), a well-characterized GPCR that binds catecholamine hormones. The receptor was bound to the partial inverse agonist carazolol and co-crystallized with a Fab made to a three-dimensional epitope formed by the third intracellular loop (ICL3), or by replacement of ICL3 with T4 lysozyme. Small crystals were obtained in lipid bicelles (β2AR-Fab) or lipidic cubic phase (β2AR-T4 lysozyme), and diffraction data were obtained using microfocus technology. The structures provide insights into the basal activity of the receptor, the structural features that enable binding of diffusible ligands, and the coupling between ligand binding and G-protein activation.
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M3 - Conference contribution
AN - SCOPUS:79952590933
SN - 9789048123384
T3 - NATO Science for Peace and Security Series A: Chemistry and Biology
SP - 217
EP - 230
BT - From Molecules to Medicines
ER -