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
Water forms 'spine of hydration' around DNA, group finds
26.05.2017 | Cornell University
How herpesviruses win the footrace against the immune system
26.05.2017 | Helmholtz-Zentrum für Infektionsforschung
Staphylococcus aureus is a feared pathogen (MRSA, multi-resistant S. aureus) due to frequent resistances against many antibiotics, especially in hospital infections. Researchers at the Paul-Ehrlich-Institut have identified immunological processes that prevent a successful immune response directed against the pathogenic agent. The delivery of bacterial proteins with RNA adjuvant or messenger RNA (mRNA) into immune cells allows the re-direction of the immune response towards an active defense against S. aureus. This could be of significant importance for the development of an effective vaccine. PLOS Pathogens has published these research results online on 25 May 2017.
Staphylococcus aureus (S. aureus) is a bacterium that colonizes by far more than half of the skin and the mucosa of adults, usually without causing infections....
Physicists from the University of Würzburg are capable of generating identical looking single light particles at the push of a button. Two new studies now demonstrate the potential this method holds.
The quantum computer has fuelled the imagination of scientists for decades: It is based on fundamentally different phenomena than a conventional computer....
An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.
We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...
Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.
Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...
An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...
24.05.2017 | Event News
23.05.2017 | Event News
22.05.2017 | Event News
26.05.2017 | Life Sciences
26.05.2017 | Life Sciences
26.05.2017 | Physics and Astronomy