GPCR engineering yields high-resolution structural insights into β2-adrenergic receptor function

Daniel M. Rosenbaum, Vadim Cherezov, Michael A. Hanson, Søren G F Rasmussen, Sun Thian Foon, Tong Sun Kobilka, Hee Jung Choi, Xiao Jie Yao, William I. Weis, Raymond C. Stevens, Brian K. Kobilka

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Abstract

The β2-adrenergic receptor (β2AR) is a well-studied prototype for heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) that respond to diffusible hormones and neurotransmitters. To overcome the structural flexibility of the β2AR and to facilitate its crystallization, we engineered a β2AR fusion protein in which T4 lysozyme (T4L) replaces most of the third intracellular loop of the GPCR ("β2AR-T4L") and showed that this protein retains near-native pharmacologic properties. Analysis of adrenergic receptor ligand-binding mutants within the context of the reported high-resolution structure of β2AR-T4L provides insights into inverse-agonist binding and the structural changes required to accommodate catecholamine agonists. Amino acids known to regulate receptor function are linked through packing interactions and a network of hydrogen bonds, suggesting a conformational pathway from the ligand-binding pocket to regions that interact with G proteins.

Original languageEnglish (US)
Pages (from-to)1266-1273
Number of pages8
JournalScience
Volume318
Issue number5854
DOIs
StatePublished - Nov 23 2007

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Cite this

Rosenbaum, D. M., Cherezov, V., Hanson, M. A., Rasmussen, S. G. F., Foon, S. T., Kobilka, T. S., Choi, H. J., Yao, X. J., Weis, W. I., Stevens, R. C., & Kobilka, B. K. (2007). GPCR engineering yields high-resolution structural insights into β2-adrenergic receptor function. Science, 318(5854), 1266-1273. https://doi.org/10.1126/science.1150609