Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New insights into the function of the main class of drug targets

04.02.2016

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.

Original article:

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

Further information

Stephan Grzesiek, Universität Basel, Biozentrum, Tel.+41 61 267 21 00, E-Mail: stephan.grzesiek@unibas.ch

Katrin Bühler | Universität Basel
Further information:
http://www.unibas.ch

More articles from Life Sciences:

nachricht Russian scientists show changes in the erythrocyte nanostructure under stress
22.02.2019 | Lobachevsky University

nachricht How the intestinal fungus Candida albicans shapes our immune system
22.02.2019 | Exzellenzcluster Präzisionsmedizin für chronische Entzündungserkrankungen

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: (Re)solving the jet/cocoon riddle of a gravitational wave event

An international research team including astronomers from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has combined radio telescopes from five continents to prove the existence of a narrow stream of material, a so-called jet, emerging from the only gravitational wave event involving two neutron stars observed so far. With its high sensitivity and excellent performance, the 100-m radio telescope in Effelsberg played an important role in the observations.

In August 2017, two neutron stars were observed colliding, producing gravitational waves that were detected by the American LIGO and European Virgo detectors....

Im Focus: Light from a roll – hybrid OLED creates innovative and functional luminous surfaces

Up to now, OLEDs have been used exclusively as a novel lighting technology for use in luminaires and lamps. However, flexible organic technology can offer much more: as an active lighting surface, it can be combined with a wide variety of materials, not just to modify but to revolutionize the functionality and design of countless existing products. To exemplify this, the Fraunhofer FEP together with the company EMDE development of light GmbH will be presenting hybrid flexible OLEDs integrated into textile designs within the EU-funded project PI-SCALE for the first time at LOPEC (March 19-21, 2019 in Munich, Germany) as examples of some of the many possible applications.

The Fraunhofer FEP, a provider of research and development services in the field of organic electronics, has long been involved in the development of...

Im Focus: Regensburg physicists watch electron transfer in a single molecule

For the first time, an international team of scientists based in Regensburg, Germany, has recorded the orbitals of single molecules in different charge states in a novel type of microscopy. The research findings are published under the title “Mapping orbital changes upon electron transfer with tunneling microscopy on insulators” in the prestigious journal “Nature”.

The building blocks of matter surrounding us are atoms and molecules. The properties of that matter, however, are often not set by these building blocks...

Im Focus: University of Konstanz gains new insights into the recent development of the human immune system

Scientists at the University of Konstanz identify fierce competition between the human immune system and bacterial pathogens

Cell biologists from the University of Konstanz shed light on a recent evolutionary process in the human immune system and publish their findings in the...

Im Focus: Transformation through Light

Laser physicists have taken snapshots of carbon molecules C₆₀ showing how they transform in intense infrared light

When carbon molecules C₆₀ are exposed to an intense infrared light, they change their ball-like structure to a more elongated version. This has now been...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Global Legal Hackathon at HAW Hamburg

11.02.2019 | Event News

The world of quantum chemistry meets in Heidelberg

30.01.2019 | Event News

Our digital society in 2040

16.01.2019 | Event News

 
Latest News

JILA researchers make coldest quantum gas of molecules

22.02.2019 | Physics and Astronomy

Understanding high efficiency of deep ultraviolet LEDs

22.02.2019 | Materials Sciences

Russian scientists show changes in the erythrocyte nanostructure under stress

22.02.2019 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>