Structure and dynamics of pteridine reductase 1: the key phenomena relevant to enzyme function and drug design

Pteridine reductase 1 (PTR1) is a folate and pterin pathway enzyme unique for pathogenic trypanosomatids. As a validated drug target, PTR1 has been the focus of recent research efforts aimed at finding more effective treatments against human parasitic diseases such as leishmaniasis or sleeping sickn...

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Bibliographic Details
Published in:European biophysics journal 2023-10, Vol.52 (6-7), p.521-532
Main Authors: Panecka-Hofman, Joanna, Poehner, Ina
Format: Article
Language:English
Subjects:
African trypanosomiasis
Binding
Biochemistry
Biological and Medical Physics
Biomedical and Life Sciences
Biophysics
Cell Biology
Design
Drug development
Dynamic structural analysis
Enzymes
Folic acid
Leishmaniasis
Life Sciences
Membrane Biology
Modelling
Molecular dynamics
Nanotechnology
Neurobiology
Parasitic diseases
Pteridine reductase 1
Reductases
Review
Substrate inhibition
Therapeutic targets
Vector-borne diseases
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Summary:Pteridine reductase 1 (PTR1) is a folate and pterin pathway enzyme unique for pathogenic trypanosomatids. As a validated drug target, PTR1 has been the focus of recent research efforts aimed at finding more effective treatments against human parasitic diseases such as leishmaniasis or sleeping sickness. Previous PTR1-centered structural studies highlighted the enzyme characteristics, such as flexible regions around the active site, highly conserved structural waters, and species-specific differences in pocket properties and dynamics, which likely impacts the binding of natural substrates and inhibitors. Furthermore, several aspects of the PTR1 function, such as the substrate inhibition phenomenon and the level of ligand binding cooperativity in the enzyme homotetramer, likely related to the global enzyme dynamics, are poorly known at the molecular level. We postulate that future drug design efforts could greatly benefit from a better understanding of these phenomena through studying both the local and global PTR1 dynamics. This review highlights the key aspects of the PTR1 structure and dynamics relevant to structure-based drug design that could be effectively investigated by modeling approaches. Particular emphasis is given to the perspective of molecular dynamics, what has been accomplished in this area to date, and how modeling could impact the PTR1-targeted drug design in the future.
ISSN:0175-7571
1432-1017
DOI:10.1007/s00249-023-01677-6