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'Fight or flight' receptor revealed

Nature Reviews Molecular Cell Biology volume 9, page 4 (2008)Cite this article

The 'fight or flight' hormone adrenaline — which is produced during times of stress — is an agonist of the β2-adrenergic receptor (β2AR), a G-protein-coupled receptor (GPCR) that mediates multiple downstream effects, including pupil dilation, blood vessel constriction and increased pulse rate. Three-dimensional structures of GPCRs are difficult to obtain because hydrophobic surfaces in the transmembrane (TM) domains and GPCR flexibility (caused by multiple conformational states that vary according to agonist binding) prevent the molecular contacts that enable protein crystallization. However, two 3D crystal structures of this 'fight or flight' receptor have now been determined using different receptor–ligand complexes.

Many GPCRs, including β2AR, have some constitutive activity even in the absence of agonist binding. Hence, β2AR activity was repressed using the inverse agonist carazolol to stabilize the β2AR structure in its inactive state, although some basal activity remained. Two different techniques were used to obtain the receptor–ligand complex for crystallization, which both provided a polar surface that promoted crystallization without altering agonist binding or preventing the conformational changes that are induced by receptor activation. Rosenbaum et al. and Cherezov et al. engineered a β2AR fusion protein in which they replaced most of the conformationally variable third intracellular loop (ICL3) of β2AR with T4 lysozyme, whereas Rasmussen et al. stabilized β2AR using an antibody that specifically binds to ICL3. Crystals of the β2AR–T4 lysozyme fusion protein and the β2AR–antibody complex were obtained under lipid conditions that mimic the membrane environment of the receptor and that also aid crystallization.

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ORIGINAL RESEARCH PAPERS

  1. Rosenbaum, D. M. et al. GPCR engineering yields high-resolution structural insights into β2-adrenergic receptor function. Science 318, 1266–1273 (2007)

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  2. Cherezov, V. et al. High-resolution crystal structure of an engineered human β2-adrenergic G protein-coupled receptor. Science 318, 1258–1265 (2007)

    Article  CAS  Google Scholar 

  3. Rasmussen, S. G. F. et al. Crystal structure of the human β2 adrenergic G-protein-coupled receptor. Nature 450, 383–387 (2007)

    Article  CAS  Google Scholar 

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'Fight or flight' receptor revealed. Nat Rev Mol Cell Biol 9, 4 (2008). https://doi.org/10.1038/nrm2326

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  • DOI: https://doi.org/10.1038/nrm2326

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