Crystal structures of the β2-adrenergic receptor

William I. Weis, Daniel M. Rosenbaum, Søren G F Rasmussen, Hee Jung Choi, Foon Sun Thian, Tong Sun Kobilka, Xiao Jie Yao, Peter W. Day, Charles Parnot, Juan Jose Fung, Venkata R P Ratnala, Brian K. Kobilka, Vadim Cherezov, Michael A Hanson, Peter Kuhn, Raymond C Stevens, Patricia C. Edwards, Gebhard F X Schertler, Manfred C Burghammer, Ruslan SanishviliRobert F. Fischetti, Asna Masood, Daniel K. Rohrer

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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.

Original languageEnglish
Title of host publicationFrom Molecules to Medicines
Number of pages14
Publication statusPublished - 2009
Externally publishedYes

Publication series

NameNATO Science for Peace and Security Series A: Chemistry and Biology
ISSN (Print)18746489

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