Structures of Trypanosome Vacuolar Soluble Pyrophosphatases: Antiparasitic Drug Targets

Yunyun Yang, Tzu Ping Ko, Chun Chi Chen, Guozhong Huang, Yingying Zheng, Weidong Liu, Iren Wang, Meng Ru Ho, Shang Te Danny Hsu, Bing O'Dowd, Hannah C. Huff, Chun Hsiang Huang, Roberto Docampo, Eric Oldfield, Rey Ting Guo

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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.

Original languageEnglish (US)
Pages (from-to)1362-1371
Number of pages10
JournalACS chemical biology
Volume11
Issue number5
DOIs
StatePublished - May 20 2016

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Yang, Y., Ko, T. P., Chen, C. C., Huang, G., Zheng, Y., Liu, W., Wang, I., Ho, M. R., Hsu, S. T. D., O'Dowd, B., Huff, H. C., Huang, C. H., Docampo, R., Oldfield, E., & Guo, R. T. (2016). Structures of Trypanosome Vacuolar Soluble Pyrophosphatases: Antiparasitic Drug Targets. ACS chemical biology, 11(5), 1362-1371. https://doi.org/10.1021/acschembio.5b00724