title: Structures of Trypanosome Vacuolar Soluble Pyrophosphatases: Antiparasitic Drug Targets.
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.
authors.affiliation: College of Biotechnology, Tianjin University of Science and Technology , Tianjin 300457, China.|Industrial Enzymes National Engineering Laboratory, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences , Tianjin, 300308, China.
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Institute of Biological Chemistry, Academia Sinica , Taipei 115, Taiwan.
authors.forename: Tzu-Ping
authors.initials: TP
authors.lastname: Ko
authors.affiliation: Industrial Enzymes National Engineering Laboratory, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences , Tianjin, 300308, China.
authors.forename: Chun-Chi
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Center for Tropical and Emerging Global Diseases, and Department of Cellular Biology, University of Georgia , Athens, Georgia 30602, United States.
authors.forename: Guozhong
authors.initials: G
authors.lastname: Huang
authors.affiliation: Industrial Enzymes National Engineering Laboratory, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences , Tianjin, 300308, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Industrial Enzymes National Engineering Laboratory, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences , Tianjin, 300308, China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Liu
authors.affiliation: Institute of Biological Chemistry, Academia Sinica , Taipei 115, Taiwan.
authors.forename: Iren
authors.initials: I
authors.lastname: Wang
authors.affiliation: Institute of Biological Chemistry, Academia Sinica , Taipei 115, Taiwan.
authors.forename: Meng-Ru
authors.initials: MR
authors.lastname: Ho
authors.affiliation: Institute of Biological Chemistry, Academia Sinica , Taipei 115, Taiwan.
authors.forename: Shang-Te Danny
authors.initials: ST
authors.lastname: Hsu
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.
authors.forename: Bing
authors.initials: B
authors.lastname: O'Dowd
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.
authors.forename: Hannah C
authors.initials: HC
authors.lastname: Huff
authors.affiliation: Industrial Enzymes National Engineering Laboratory, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences , Tianjin, 300308, China.
authors.forename: Chun-Hsiang
authors.initials: CH
authors.lastname: Huang
authors.affiliation: Center for Tropical and Emerging Global Diseases, and Department of Cellular Biology, University of Georgia , Athens, Georgia 30602, United States.
authors.forename: Roberto
authors.initials: R
authors.lastname: Docampo
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.
authors.forename: Eric
authors.initials: E
authors.lastname: Oldfield
authors.affiliation: Industrial Enzymes National Engineering Laboratory, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences , Tianjin, 300308, China.
authors.forename: Rey-Ting
authors.initials: RT
authors.lastname: Guo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000977:Antiparasitic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002417:Cattle; D014355:Chagas Disease / Q000188:drug therapy / Q000469:parasitology; D018360:Crystallography, X-Ray; D004164:Diphosphonates / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D011755:Pyrophosphatases / Q000737:chemistry* / Q000378:metabolism; D014346:Trypanosoma brucei brucei / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D014349:Trypanosoma cruzi / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D014354:Trypanosomiasis, Bovine / Q000188:drug therapy / Q000469:parasitology
chemical_list: D000977:Antiparasitic Agents; D004164:Diphosphonates; D011755:Pyrophosphatases