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Visualising the architecture of G-protein coupled receptor interactions
The architecture of the key regulatory protein beta-arrestin in complex with a G-protein coupled receptor (GPCR) has been elucidated by a combination of electron microscopy and mass spectrometry in a paper published in the journal Nature. The study comes from a research team from Duke Medicine, the University of Michigan and Stanford University. The study should help advance understanding of how cells transmit signals and how signalling is controlled in the body's response to stimuli including light and pain.

GPCRs are seven transmembrane spanning structures which operate in a multitude of cell signalling pathways. As a group, they represent the largest drug target family for human diseases as disparate as cardiovascular disease, neurological disease and cancer. Co –senior author on the paper, Dr Robert J. Lefkowitz of Duke University School of Medicine and the Howard Hughes Medical Institute, explains the importance of insights into the structure of GPCRs: "It is crucial to visualize how these receptors work to fully appreciate how our bodies respond to a wide array of stimuli, including light, hormones and various chemicals." Dr Lefkowitz shared the Nobel Prize for Chemistry in 2012 with one of the other senior co-authors on the paper, Dr Brian K. Kobilka, of Stanford University School of Medicine, for their work on GPCRs.

In this paper, the authors presented a visualisation of the protein beta-arrestin in complex with the ‘fight-or-flight’ associated beta 2-adrenergic receptor. Beta-arrestins function to desensitise and therefore cap GPCR signalling and to initiate a new wave of GPCR-independent signalling. Another co-senior author, Dr Georgios Skiniotis of the University of Michigan further explains: "Arrestin's primary role is to put the cap on GPCR signaling. Elucidating the structure of this complex is crucial for understanding how the receptors are desensitized in order to prevent aberrant signalling." The research team formed and purified a functional human β2AR–β-arrestin-1 complex. Using mass spectrometry, cross-linking analysis and electron microscopy, they were able to confirm a previously suspected but not demonstrated bimodal binding, involving two separate interactions between beta-arrestin and both the intracellular carboxy tail of the GPCR and with its 7 transmembrane core.

The authors now plan to bring X-ray crystallography into play in order to attain atomic level insights into this architecture. These details could then be harnessed in experiments aimed at novel drug design and for gaining improved understanding of the fundamentals of GPCR biology. Co-lead author Arun K. Shukla concludes: “This is just a start and there is a long way to go…We have to visualize similar complexes of other GPCRs to develop a comprehensive understanding of this family of receptors."


Shukla, A.K. et al (2014). Visualization of arrestin recruitment by a G-protein-coupled receptor. Nature (June 22 2014); doi:10.1038/nature13430

Press release: Duke University Medical Center; available from
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