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Press release

28.05.2018

Communication in the cell: important step of signal transmission elucidated

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Computer simulation GPCR-arrestin complex
Molecular structure of arrestin (purple/cyan) bound to a GPCR (red) in the cell membrane (horizontal black lines). The published study investigated how the „core“ and „tail“ of the receptor induce changes in the molecular structure of arrestin (i.e. activation) and thereby stimulate receptor binding by arrestin. Copyright: Naomi Latorraca and Ron Dror/Stanford University.

The effectiveness of new drugs depends crucially on a fundamental understanding of the complex processes within the cells of the body. Scientists from Stanford University in California and the CharitéUniversitätsmedizin Berlin have deciphered an important molecular step of cellular signal transmission and published in the journal Nature*. Their findings could help the development of specific drugs against various diseases, such as asthma and high blood pressure.

Signals are often transmitted within the body with the help of messenger compounds. These molecules bind to specific docking sites on the surface of the target cell and initiate a series of sequential reactions inside the cell. The largest family of docking sites are the so-called G protein-coupled receptors (GPCR). GPCRs are not only involved in the processing of sensory stimuli but are also an important drug target for the treatment of diseases such as asthma, schizophrenia, hypertension and cancer. 30 to 40 percent of all currently prescribed drugs for these diseases target GPCRs. The functioning of GPCRs in the cell depends on how the receptors interact with different proteins in the cell. One of these proteins is arrestin. It controls which signalling pathways are activated by different receptors and their different binding partners.

The aim of the study was to elucidate the molecular mechanism of activation of the GPCR-arrestin complex. Computer simulations and fluorescence spectroscopy were used to monitor changes in the molecular structure of arrestin bound to the receptor. The results allow unprecedented detailed insight into the molecular interactions of GPCR and arrestin during signal transduction in the cell. Regarding the importance of this research in basic medicine, Dr. Martha Sommer from the Charité Institute of Medical Physics and Biophysics says, „The better we understand how these receptors interact with binding partners inside the cell, the better we are able to develop drugs that have the desired therapeutic effect but avoid unwanted and harmful side effects.“ Subsequent studies are designed to further sharpen our view of the interaction between GPCRs and arrestin, thereby enabling the development of drugs that specifically target this signalling pathway.

* Latorraca NR, Wang JK, Bauer B, Townshend RJL, Hollingsworth SA, Olivieri JE, Xu HE, Sommer ME, Dror RO. Molecular mechanism of GPCR-mediated arrestin activation. Nature. 2018 May 2. DOI: 10.1038/s41586-018-0077-3.

This study is a cooperation between the Charité and Prof. Ron Dror at Stanford University in California, USA. The work group „Arrestin“ at the Charité is supported by the German Research Foundation (DFG), through the Collaborative Research Centre 740: „From Molecules to Modules: Organization and Dynamics of Cellular Functional Units“.

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Institute of Medical Physics and Biophysics

Workgroup Arrestin at Institute of Medical Physics and Biophysics

Original publication at Nature

Contact

Dr. Martha Sommer
Institute of Medical Physics and Biophysics
CharitéUniversitätsmedizin Berlin         
t: +49 30 450 524 200



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