Seminarium z fizyki biologicznej i bioinformatyki
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2022-05-25 (15:15) 
Dr Joanna Panecka-Hofman (Zakład Biofizyki, Wydział Fizyki UW, Warszawa)
The global and local dynamics of a homotetrameric folate pathway enzyme - pteridine reductase 1 - the target for anti-trypanosomatid drug design
https://zoom.us/j/91976153012?pwd=azNiMWE4UnhPN3lRQlY2UHZHOXVkQT09
Meeting ID: 919 7615 3012
Passcode: 747922
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Bogdan Lesyng (UW)
Anna Niedźwiecka (IF PAN)
Piotr Zielenkiewicz (IBB)
ABSTRACT
Inhibiting the folate pathway of trypanosomatid parasites, which cause life-threatening human diseases such as leishmaniases, is a potentially useful drug design approach. Pteridine reductase 1 (PTR1) is a key trypanosomatid-specific enzyme of this pathway that needs to be targeted. The role of the PTR1 homotetramer local and global dynamics in its enzymatic function and inhibitor binding is poorly understood. Experimental data suggest that the PTR1 substrate and inhibitor binding may be regulated by the long-distance coupling between four binding sites in the homotetramer. Therefore, computational methods were applied to characterize the enzyme dynamical properties and its interactions with selected ligands. Normal mode analysis demonstrated correlated movements of substrate loops flanking the binding sites of the homotetrameric enzyme. Molecular dynamics study provided insights into the interactions of substrates, products and the model inhibitor with PTR1, and the potential mechanism of the, so-called, substrate inhibition phenomenon. Finally, a non-equilibrium method, Rotamerically Induced Perturbations, revealed flexibility hot-spots in the PTR1 homotetramer, and different levels of dynamical coupling between the particular PTR1 monomers.
Meeting ID: 919 7615 3012
Passcode: 747922
One tap mobile
+48223073488,,91976153012#,,,,*747922# Poland
+48223987356,,91976153012#,,,,*747922# Poland
Dial by your location
+48 22 307 3488 Poland
+48 22 398 7356 Poland
+48 22 306 5342 Poland
Join by Skype for Business
https://zoom.us/skype/91976153012
Bogdan Lesyng (UW)
Anna Niedźwiecka (IF PAN)
Piotr Zielenkiewicz (IBB)
ABSTRACT
Inhibiting the folate pathway of trypanosomatid parasites, which cause life-threatening human diseases such as leishmaniases, is a potentially useful drug design approach. Pteridine reductase 1 (PTR1) is a key trypanosomatid-specific enzyme of this pathway that needs to be targeted. The role of the PTR1 homotetramer local and global dynamics in its enzymatic function and inhibitor binding is poorly understood. Experimental data suggest that the PTR1 substrate and inhibitor binding may be regulated by the long-distance coupling between four binding sites in the homotetramer. Therefore, computational methods were applied to characterize the enzyme dynamical properties and its interactions with selected ligands. Normal mode analysis demonstrated correlated movements of substrate loops flanking the binding sites of the homotetrameric enzyme. Molecular dynamics study provided insights into the interactions of substrates, products and the model inhibitor with PTR1, and the potential mechanism of the, so-called, substrate inhibition phenomenon. Finally, a non-equilibrium method, Rotamerically Induced Perturbations, revealed flexibility hot-spots in the PTR1 homotetramer, and different levels of dynamical coupling between the particular PTR1 monomers.