# GPCR Engineering Yields High-Resolution Structural Insights into β2-Adrenergic Receptor Function

@article{Rosenbaum2007GPCREY,
title={GPCR Engineering Yields High-Resolution Structural Insights into $\beta$2-Adrenergic Receptor Function},
author={Daniel M. Rosenbaum and Vadim Cherezov and Michael A. Hanson and S{\o}ren G F Rasmussen and Foon Sun Thian and Tong Sun Kobilka and Hee-Jung Choi and Xiao Jie Yao and William I. Weis and Raymond C. Stevens and Brian K. Kobilka},
journal={Science},
year={2007},
volume={318},
pages={1266 - 1273}
}
• Published 23 November 2007
• Biology, Chemistry
• Science
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…
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## References

SHOWING 1-10 OF 81 REFERENCES

• Biology, Chemistry
Science
• 2007
Although the location of carazolol in the β2-adrenergic receptor is very similar to that of retinal in rhodopsin, structural differences in the ligand-binding site and other regions highlight the challenges in using rhodopin as a template model for this large receptor family.
• Biology, Chemistry
Nature chemical biology
• 2006
It is found that most partial agonists were as effective as full agonists in disrupting the ionic lock, and disruption of this important molecular switch is necessary, but not sufficient, for full activation of the β2-AR.
• Biology, Chemistry
Proceedings of the National Academy of Sciences of the United States of America
• 2001
The authors' studies, when compared with studies of activation in rhodopsin, indicate a general mechanism for GPCR activation; however, a notable difference is the relatively slow kinetics of the conformational changes in the β2AR, which may reflect the different energetics of activation by diffusible ligands.
• Biology, Chemistry
Journal of Biological Chemistry
• 2005
Catechol is used as a molecular probe to identify mechanistic differences between β2AR activation by catecholamine agonists, such as isoproterenol, and by the structurally related non-catechol partial agonist salbutamol, showing unexpected differences in binding and activation by structurally similar agonists and partial agonists.
• Biology, Chemistry
The EMBO journal
• 1997
Findings suggest that IANBD bound to 125Cys and 285Cys are exposed to a more polar environment upon agonist binding, and indicate that movements of transmembrane segments III and VI are involved in activation of G protein‐coupled receptors.
• Biology, Chemistry
The Journal of Biological Chemistry
• 2001
Monitoring ligand-induced conformational changes in the G protein-coupling domain of the β2 adrenergic receptor provides new insight into the structural consequence of antagonist binding and the basis of agonism and partial agonism.
• Biology, Chemistry
The Journal of biological chemistry
• 2004
A mechanistic model for GPCR activation where contacts between the receptor and structural determinants of the agonist stabilize a succession of conformational states with distinct cellular functions is supported.
• Biology, Chemistry
Proceedings of the National Academy of Sciences
• 2007
To determine the role of group-conserved residues in the β2-adrenergic receptor (β2-AR), amino acid replacements guided by molecular modeling were carried out at key positions in transmembrane helices H2–H4 and allow insights into the roles of these residues in GPCR structure and function.
• Biology, Chemistry
The Journal of Biological Chemistry
• 1997
It is proposed that the mutation that confers constitutive activity to the β2 adrenergic receptor removes some stabilizing conformational constraints, allowing CAM to more readily undergo transitions between the inactive and the active states and making the receptor more susceptible to denaturation.
• Biology, Chemistry
Proceedings of the National Academy of Sciences of the United States of America
• 1997
Evidence is provided for an essential role of this motif in the agonist-induced internalization of the beta2-adrenergic receptor in the L339,340A double mutant and reduced in the two single mutants.