ArticleACS chemical biology2016
Structures of Trypanosome Vacuolar Soluble Pyrophosphatases: Antiparasitic Drug Targets.
Article in ACS chemical biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 18 citations in OpenAlex.
- Advances in the cellular biology, biochemistry, and molecular biology of acidocalcisomes.Microbiology and molecular biology reviews : MMBR · 2024Review
- New insights into the role of acidocalcisomes in trypanosomatids.The Journal of eukaryotic microbiology · 2022Review
- Molecular characterization and transcriptional regulation of two types of HScientific reports · 2021Article
- The IPBiochimica et biophysica acta. Molecular cell research · 2021Review
- Forward Genetics in African Trypanosomes.Methods in molecular biology (Clifton, N.J.) · 2020Article
- NUDIX hydrolases with inorganic polyphosphate exo- and endopolyphosphatase activities in the glycosome, cytosol and nucleus ofBioscience reports · 2019Article
- Article
- 5-Diphosphoinositol pentakisphosphate (5-IPThe Journal of biological chemistry · 2018Article
- Inorganic polyphosphate interacts with nucleolar and glycosomal proteins in trypanosomatids.Molecular microbiology · 2018Article
- Synthesis of medronic acid monoesters and their purification by high-performance countercurrent chromatography or by hydroxyapatite.Beilstein journal of organic chemistry · 2016Article
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Authors and funding
15 authors at 5 institutions in 3 countries.
Funding
Abstract
Trypanosomatid parasites are the causative agents of many neglected tropical diseases, including the leishmaniases, Chagas disease, and human African trypanosomiasis. They exploit unusual vacuolar soluble pyrophosphatases (VSPs), absent in humans, for cell growth and virulence and, as such, are drug targets. Here, we report the crystal structures of VSP1s from Trypanosoma cruzi and T. brucei, together with that of the T. cruzi protein bound to a bisphosphonate inhibitor. Both VSP1s form a hybrid structure containing an (N-terminal) EF-hand domain fused to a (C-terminal) pyrophosphatase domain. The two domains are connected via an extended loop of about 17 residues. Crystallographic analysis and size exclusion chromatography indicate that the VSP1s form tetramers containing head-to-tail dimers. Phosphate and diphosphate ligands bind in the PPase substrate-binding pocket and interact with several conserved residues, and a bisphosphonate inhibitor (BPH-1260) binds to the same site. On the basis of Cytoscape and other bioinformatics analyses, it is apparent that similar folds will be found in most if not all trypanosomatid VSP1s, including those found in insects (Angomonas deanei, Strigomonas culicis), plant pathogens (Phytomonas spp.), and Leishmania spp. Overall, the results are of general interest since they open the way to structure-based drug design for many of the neglected tropical diseases.
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