title: The Cryptosporidium parvum kinome.
abstract: BACKGROUND
  Hundreds of millions of people are infected with cryptosporidiosis annually, with immunocompromised individuals suffering debilitating symptoms and children in socioeconomically challenged regions at risk of repeated infections. There is currently no effective drug available. In order to facilitate the pursuit of anti-cryptosporidiosis targets and compounds, our study spans the classification of the Cryptosporidium parvum kinome and the structural and biochemical characterization of representatives from the CDPK family and a MAP kinase.
  
  
  RESULTS
  The C. parvum kinome comprises over 70 members, some of which may be promising drug targets. These C. parvum protein kinases include members in the AGC, Atypical, CaMK, CK1, CMGC, and TKL groups; however, almost 35% could only be classified as OPK (other protein kinases). In addition, about 25% of the kinases identified did not have any known orthologues outside of Cryptosporidium spp. Comparison of specific kinases with their Plasmodium falciparum and Toxoplasma gondii orthologues revealed some distinct characteristics within the C. parvum kinome, including potential targets and opportunities for drug design. Structural and biochemical analysis of 4 representatives of the CaMK group and a MAP kinase confirms features that may be exploited in inhibitor design. Indeed, screening CpCDPK1 against a library of kinase inhibitors yielded a set of the pyrazolopyrimidine derivatives (PP1-derivatives) with IC₅₀ values of < 10 nM. The binding of a PP1-derivative is further described by an inhibitor-bound crystal structure of CpCDPK1. In addition, structural analysis of CpCDPK4 identified an unprecedented Zn-finger within the CDPK kinase domain that may have implications for its regulation.
  
  
  CONCLUSIONS
  Identification and comparison of the C. parvum protein kinases against other parasitic kinases shows how orthologue- and family-based research can be used to facilitate characterization of promising drug targets and the search for new drugs.
authors.affiliation: Structural Genomics Consortium, University of Toronto, MaRS South Tower, Floor 7, 101 College St, Toronto, Ontario M5G 1L7, Canada. jdartz@gmail.com
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Artz
authors.forename: Amy K
authors.initials: AK
authors.lastname: Wernimont
authors.forename: Abdellah
authors.initials: A
authors.lastname: Allali-Hassani
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Mehrnaz
authors.initials: M
authors.lastname: Amani
authors.forename: Yu-Hui
authors.initials: YH
authors.lastname: Lin
authors.forename: Guillermo
authors.initials: G
authors.lastname: Senisterra
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Wasney
authors.forename: Oleg
authors.initials: O
authors.lastname: Fedorov
authors.forename: Oliver
authors.initials: O
authors.lastname: King
authors.forename: Annette
authors.initials: A
authors.lastname: Roos
authors.forename: Vlad V
authors.initials: VV
authors.lastname: Lunin
authors.forename: Wei
authors.initials: W
authors.lastname: Qiu
authors.forename: Patrick
authors.initials: P
authors.lastname: Finerty
authors.forename: Ashley
authors.initials: A
authors.lastname: Hutchinson
authors.forename: Irene
authors.initials: I
authors.lastname: Chau
authors.forename: Frank
authors.initials: F
authors.lastname: von Delft
authors.forename: Farrell
authors.initials: F
authors.lastname: MacKenzie
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Lew
authors.forename: Ivona
authors.initials: I
authors.lastname: Kozieradzki
authors.forename: Masoud
authors.initials: M
authors.lastname: Vedadi
authors.forename: Matthieu
authors.initials: M
authors.lastname: Schapira
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.forename: Kevan
authors.initials: K
authors.lastname: Shokat
authors.forename: Tom
authors.initials: T
authors.lastname: Heightman
authors.forename: Raymond
authors.initials: R
authors.lastname: Hui
mesh_terms: D016785:Cryptosporidium parvum / Q000201:enzymology* / Q000235:genetics; D030562:Databases, Protein; D010963:Plasmodium falciparum / Q000201:enzymology; D011494:Protein Kinases / Q000032:analysis* / Q000145:classification / Q000235:genetics; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000032:analysis* / Q000145:classification / Q000235:genetics; D014122:Toxoplasma / Q000201:enzymology
chemical_list: D015800:Protozoan Proteins; D011494:Protein Kinases