New Study Reveals Mechanism for Regulating Enzyme Activity in Promising Drug Target
Researchers from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) have made an exciting discovery in the field of enzyme activity regulation. Their findings, published in the journal Science Advances, shed light on the key role played by the dynamics of a gate in rhomboid proteases, potential targets for novel drugs.
Rhomboid proteases are enzymes located in the cell membrane and are involved in various biological processes in the human body. They have been implicated in diseases such as Parkinson’s disease, malaria, and cancer, making them attractive targets for drug development.
In a groundbreaking study, Professor Adam Lange’s research group produced dynamic images of rhomboid proteases using solid-state NMR spectroscopy in 2019. These images confirmed the opening of a gate in the enzymes when other proteins are cleaved. Building on this discovery, the FMP researchers aimed to explore the importance of this mechanism in regulating enzyme activity.
Using a combination of experimental and theoretical techniques, including solid-state NMR spectroscopy, biophysical methods, biochemical functional assays, and molecular dynamics simulations, the researchers demonstrated a clear correlation between the dynamics of the gate and the enzyme activity.
To further investigate this correlation, the researchers biochemically modified rhomboid proteases from E. coli bacteria, producing mutants with either a movable or closed gate. The results were intriguing: mutations that facilitated the opening of the gate led to an increase in enzyme activity, while a closed gate resulted in the cessation of activity.
To support and extend their experimental results, molecular dynamics simulations were conducted. These simulations provided valuable insights into the necessary width of the gate to allow substrates to pass through.
The implications of this study could be significant for the development of new compounds targeting rhomboid proteases. By better understanding the gate dynamics and its relationship to enzyme activity, researchers may be able to contribute to advancements in treating diseases associated with these enzymes.
With this research, FMP researchers have made an important contribution to the field of enzyme activity regulation in rhomboid proteases. Their findings provide crucial insights that could pave the way for new drugs and treatments for a range of diseases.
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