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

Research output: Contribution to journalArticlepeer-review

1110 Scopus citations

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

ASJC Scopus subject areas

  • General

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