New insights for drug research: Breaking the coupling process

Date:
October 6, 2020
Source:
University of Freiburg
Summary:
Real-time observation of signal transmission in proteins provides
new insights for drug research.



FULL STORY ========================================================================== Proteins transduce information and signals within the human body
by changes in their structures. For example, hormones binding to
their target proteins cause a structural change which in turn opens
new binding sites for other proteins elsewhere on the surface of the
protein. Researchers refer to this coupling of different, distant binding
sites as allostery. An interruption of this coupling leads to signals
not being passed on.


==========================================================================
This can be achieved by molecules specifically designed for this
purpose, which thereby obtain pharmacological effects as analgesics or chemotherapeutic agents. To selectively design such molecules, scientists
need to learn more about the possible mechanisms of allostery. A team led
by Prof. Dr. Gerhard Stock from the Biomolecular Dynamics group at the Institute of Physics at the University of Freiburg and Prof. Dr. Peter
Hamm from the Institute of Chemistry at the University of Zurich,
Switzerland provides important insights into the molecular details of
allostery in the journal PNAS.

The researchers tracked time-resolved allosteric changes in the test
protein PDZ2, which are caused by the binding of a peptide ligand. To
this end, the research group at the University of Zurich performed time-resolved vibrational spectroscopy, while the physicists at the
University of Freiburg simulated the corresponding changes on an atomistic level using the bwHPC cluster BinAC at Tu"bingen. This combination enabled
the scientists to understand how a change in the ligand binding mode
induces protein structure changes passing through the protein with atomic resolution and a time scale range from picoseconds to microseconds. The real-time observation of signal transduction in proteins showed that
allostery is based on changes in both the structure and dynamics of the protein, which exhibits hierarchical dynamics, where a structural change
takes about ten times longer than a preceding change.


========================================================================== Story Source: Materials provided by University_of_Freiburg. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Olga Bozovic, Claudio Zanobini, Adnan Gulzar, Brankica Jankovic,
David
Buhrke, Matthias Post, Steffen Wolf, Gerhard Stock, Peter
Hamm. Real-time observation of ligand-induced allosteric transitions
in a PDZ domain.

Proceedings of the National Academy of Sciences, 2020; 202012999
DOI: 10.1073/pnas.2012999117 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/10/201006114219.htm

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