About thirty percent of all medical drugs such as beta-blockers or antidepressants interact with certain types of cell surface proteins called G protein coupled receptors. In collaboration with researchers from the Paul Scherrer Institute, the group of Prof. Stephan Grzesiek at the Biozentrum of the University of Basel has now elucidated in detail how the structure of such a receptor changes when drugs bind and how the structural change transmits a signal to the cellular interior. These results have recently been published in “Nature”.
A wide variety of drugs such as beta-blockers against high blood pressure or drugs against allergies, cancer, Parkinson’s disease, HIV and others bind to cell surface proteins which belong to the family of G protein coupled receptors. The drug binding transmits a signal to the inside of the cell. Despite the fact that many structures of these receptors are known, it remained unclear how the signal is transmitted to the intracellular inside.
The NMR technology detects signals (shown as contour lines) from individual atoms (blue spheres) of the β1-adrenergic G protein coupled membrane receptor (grey ribbon diagram). Upon binding of drugs such as adrenalin (black chemical structure) the signals from the atoms change (from blue to yellow/red contours). This change allows the effect of drug binding to be followed throughout the receptor. © University of Basel, Biozentrum
To better understand the signal transduction function, Prof. Stephan Grzesiek’s team at the Biozentrum of the University of Basel, together with researchers from the Paul Scherrer Institute (PSI) have studied in detail one receptor – the β1-adrenergic receptor. Using Nuclear Magnetic Resonance spectroscopy (NMR), the scientists have been able to follow the motions of this receptor in response to various drugs, and have thus obtained unprecedented detailed insights into the general mechanism of G protein coupled receptor function.
Structural changes provide details on receptor function
The β1-adrenergic receptor is a protein embedded in the membrane of cardiac cells. It translates the binding of extracellular drug molecules into the activation of intracellular proteins. The hormone noradrenaline, for example, induces a signaling cascade in the cell, which at the end increases heart rate and blood pressure. So-called beta-blockers impede these effects by preventing the hormone from binding to the adrenergic receptor. Thereby, they reduce the heart rate. Structural details of the signal transduction caused by such receptor-ligand interactions have so far remained unclear.
“We have applied high resolution NMR to analyze the structural changes of the β1-adrenergic receptor upon binding of various drugs”, explains first author Shin Isogai. “We could observe how the receptor recognizes the binding partner, interprets its chemical structure and transmits this information to the inside of the cell by changing its structure. This insight into the functionality of the β1-adrenergic receptor at the atomic level can be applied to the whole family of G protein coupled receptors, which are well known as important drug targets.”
Prediction of drug efficacy
Using the NMR observation of the atomic nuclei, the scientists could see how deep the drugs insert into the receptor from the outside, how the drug pushes certain groups away and how it transmits this mechanical signal to the inside. Thus they identified crucial mechanical connections for the signal transmission within the receptor structure. The NMR signals also revealed the binding strength of the drugs and their potency to trigger an intracellular response. In fact, they could follow how a model protein for the intracellular response binds to the activated receptor.
“We are very happy that we could see these details. The receptors are notoriously difficult to study. Many researchers have tried for more than a decade”, emphasizes Isogai. “Now we can apply this method to see the function of individual amino acids and to study other receptors.” In the future, the NMR method may also be used for drug screening and drug development.
Shin Isogai, Xavier Deupi, Christian Opitz, Franziska M. Heydenreich, Florian Brueckner, Gebhard F.X. Schertler, Dmitry B. Veprintsev and Stephan Grzesiek. Backbone NMR reveals allosteric signal transduction networks in the β1-adrenergic receptor. Nature; published online 3 February 2016.| doi: 10.1038/nature16577
Stephan Grzesiek, Universität Basel, Biozentrum, Tel.+41 61 267 21 00, E-Mail: email@example.com
Katrin Bühler | Universität Basel
Toward a 'smart' patch that automatically delivers insulin when needed
18.01.2017 | American Chemical Society
127 at one blow...
18.01.2017 | Stiftung Zoologisches Forschungsmuseum Alexander Koenig, Leibniz-Institut für Biodiversität der Tiere
Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).
Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...
10.01.2017 | Event News
09.01.2017 | Event News
05.01.2017 | Event News
18.01.2017 | Power and Electrical Engineering
18.01.2017 | Materials Sciences
18.01.2017 | Life Sciences