Crystal structure of glycerol kinase from Trypanosoma cruzi, a potential molecular target in Chagas disease.
Professor Dr Grzegorz Dubin [1]
Molecular Tour
Chagas disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. The significant global health burden and limited treatment options call for the development of new and effective drugs. Recent research has identified certain metabolic enzymes as promising targets for drug development. Among these, glycerol kinase (GK), a key enzyme in glycerol metabolism, has drawn attention due to its potential role in the parasite’s survival and proliferation.
In our study, we have elucidated the crystal structure of GK from T. cruzi, providing critical insights into its function and potential as a drug target. Through comparative sequence analysis, we explored the evolutionary conservation and unique features of this enzyme, which set the stage for a deeper understanding of its role in the parasite's metabolism. Structural analysis allowed a detailed description of the glycerol binding pocket, while superimposition with GK structure from closely related Trypanosoma brucei revealed a strategic location for ATP binding. Notably, the overall fold of the structure, including the dimerization interface, was characterized, highlighting regions crucial for the enzyme's stability and function.
Furthermore, by comparative assessment, we pinpointed a potential regulatory site that may serve as a target for selective inhibition, providing a pathway to design drugs that specifically target the parasite without affecting the host.
Despite our efforts to form a complex with the Pex5 protein, known for its role in peroxisomal protein import, no interaction was observed. This lack of interaction can be attributed to structural constraints, suggesting that the binding sites or conformations required for complex formation are incompatible. This finding emphasizes the specificity of GK interactions and opens avenues for exploring other potential regulatory mechanisms or interacting partners.
References
- ↑ Lipiński O, Sonani RR, Dubin G. Crystal structure of glycerol kinase from Trypanosoma cruzi, a potential molecular target in Chagas disease. Acta Crystallogr D Struct Biol. 2024 Aug 1;80(Pt 8):629-638. PMID:39052317 doi:10.1107/S2059798324006594
