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 Princeton researchers explore how a carbon-fixing organelle forms via phase separation
13.09.2019 | Princeton University

nachricht The working of a molecular string phone
13.09.2019 | Max-Planck-Institut für Struktur und Dynamik der Materie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: The working of a molecular string phone

Researchers from the Department of Atomically Resolved Dynamics of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg, the University of Potsdam (both in Germany) and the University of Toronto (Canada) have pieced together a detailed time-lapse movie revealing all the major steps during the catalytic cycle of an enzyme. Surprisingly, the communication between the protein units is accomplished via a water-network akin to a string telephone. This communication is aligned with a ‘breathing’ motion, that is the expansion and contraction of the protein.

This time-lapse sequence of structures reveals dynamic motions as a fundamental element in the molecular foundations of biology.

Im Focus: Milestones on the Way to the Nuclear Clock

Two research teams have succeeded simultaneously in measuring the long-sought Thorium nuclear transition, which enables extremely precise nuclear clocks. TU Wien (Vienna) is part of both teams.

If you want to build the most accurate clock in the world, you need something that "ticks" very fast and extremely precise. In an atomic clock, electrons are...

Im Focus: Graphene sets the stage for the next generation of THz astronomy detectors

Researchers from Chalmers University of Technology have demonstrated a detector made from graphene that could revolutionize the sensors used in next-generation space telescopes. The findings were recently published in the scientific journal Nature Astronomy.

Beyond superconductors, there are few materials that can fulfill the requirements needed for making ultra-sensitive and fast terahertz (THz) detectors for...

Im Focus: Physicists from Stuttgart prove the existence of a supersolid state of matte

A supersolid is a state of matter that can be described in simplified terms as being solid and liquid at the same time. In recent years, extensive efforts have been devoted to the detection of this exotic quantum matter. A research team led by Tilman Pfau and Tim Langen at the 5th Institute of Physics of the University of Stuttgart has succeeded in proving experimentally that the long-sought supersolid state of matter exists. The researchers report their results in Nature magazine.

In our everyday lives, we are familiar with matter existing in three different states: solid, liquid, or gas. However, if matter is cooled down to extremely...

Im Focus: World record for tandem perovskite-CIGS solar cell

A team headed by Prof. Steve Albrecht from the HZB will present a new world-record tandem solar cell at EU PVSEC, the world's largest international photovoltaic and solar energy conference and exhibition, in Marseille, France on September 11, 2019. This tandem solar cell combines the semiconducting materials perovskite and CIGS and achieves a certified efficiency of 23.26 per cent. One reason for this success lies in the cell’s intermediate layer of organic molecules: they self-organise to cover even rough semiconductor surfaces. Two patents have been filed for these layers.

Perovskite-based solar cells have experienced an incredibly rapid increase in efficiency over the last ten years. The combination of perovskites with classical...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Society 5.0: putting humans at the heart of digitalisation

10.09.2019 | Event News

Interspeech 2019 conference: Alexa and Siri in Graz

04.09.2019 | Event News

AI for Laser Technology Conference: optimizing the use of lasers with artificial intelligence

29.08.2019 | Event News

 
Latest News

Low sea-ice cover in the Arctic

13.09.2019 | Earth Sciences

Researchers produce synthetic Hall Effect to achieve one-way radio transmission

13.09.2019 | Power and Electrical Engineering

Penn engineers' new topological insulator reroutes photonic 'traffic' on the fly

13.09.2019 | Power and Electrical Engineering

VideoLinks
Science & Research
Overview of more VideoLinks >>>