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 'Lipid asymmetry' plays key role in activating immune cells
20.02.2018 | Biophysical Society

nachricht New printing technique uses cells and molecules to recreate biological structures
20.02.2018 | Queen Mary University of London

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: In best circles: First integrated circuit from self-assembled polymer

For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.

In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...

Im Focus: Demonstration of a single molecule piezoelectric effect

Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale

Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...

Im Focus: Hybrid optics bring color imaging using ultrathin metalenses into focus

For photographers and scientists, lenses are lifesavers. They reflect and refract light, making possible the imaging systems that drive discovery through the microscope and preserve history through cameras.

But today's glass-based lenses are bulky and resist miniaturization. Next-generation technologies, such as ultrathin cameras or tiny microscopes, require...

Im Focus: Stem cell divisions in the adult brain seen for the first time

Scientists from the University of Zurich have succeeded for the first time in tracking individual stem cells and their neuronal progeny over months within the intact adult brain. This study sheds light on how new neurons are produced throughout life.

The generation of new nerve cells was once thought to taper off at the end of embryonic development. However, recent research has shown that the adult brain...

Im Focus: Interference as a new method for cooling quantum devices

Theoretical physicists propose to use negative interference to control heat flow in quantum devices. Study published in Physical Review Letters

Quantum computer parts are sensitive and need to be cooled to very low temperatures. Their tiny size makes them particularly susceptible to a temperature...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

2nd International Conference on High Temperature Shape Memory Alloys (HTSMAs)

15.02.2018 | Event News

Aachen DC Grid Summit 2018

13.02.2018 | Event News

How Global Climate Policy Can Learn from the Energy Transition

12.02.2018 | Event News

 
Latest News

'Lipid asymmetry' plays key role in activating immune cells

20.02.2018 | Life Sciences

MRI technique differentiates benign breast lesions from malignancies

20.02.2018 | Medical Engineering

Major discovery in controlling quantum states of single atoms

20.02.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>