Article abstract


Nature Chemical Biology 4, 347 - 356 (2008)
Published online: 4 May 2008 | doi:10.1038/nchembio.87

Gene expression signatures and small-molecule compounds link a protein kinase to Plasmodium falciparum motility

Nobutaka Kato1,2, Tomoyo Sakata2, Ghislain Breton1, Karine G Le Roch2, Advait Nagle2, Carsten Andersen2, Badry Bursulaya2, Kerstin Henson1,2, Jeffrey Johnson1, Kota Arun Kumar3, Felix Marr1, Daniel Mason2, Case McNamara2, David Plouffe2, Vandana Ramachandran1, Muriel Spooner2, Tove Tuntland2, Yingyao Zhou2, Eric C Peters2, Arnab Chatterjee2, Peter G Schultz1,2, Gary E Ward4, Nathanael Gray2, Jeffrey Harper5 & Elizabeth A Winzeler1,2


Calcium-dependent protein kinases play a crucial role in intracellular calcium signaling in plants, some algae and protozoa. In Plasmodium falciparum, calcium-dependent protein kinase 1 (PfCDPK1) is expressed during schizogony in the erythrocytic stage as well as in the sporozoite stage. It is coexpressed with genes that encode the parasite motor complex, a cellular component required for parasite invasion of host cells, parasite motility and potentially cytokinesis. A targeted gene-disruption approach demonstrated that pfcdpk1 seems to be essential for parasite viability. An in vitro biochemical screen using recombinant PfCDPK1 against a library of 20,000 compounds resulted in the identification of a series of structurally related 2,6,9-trisubstituted purines. Compound treatment caused sudden developmental arrest at the late schizont stage in P. falciparum and a large reduction in intracellular parasites in Toxoplasma gondii, which suggests a possible role for PfCDPK1 in regulation of parasite motility during egress and invasion.

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  1. Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, ICND202 La Jolla, California 92037, USA.
  2. Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
  3. Michael Heidelberger Division of Immunology, Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
  4. Department of Microbiology and Molecular Genetics, University of Vermont, 95 Carrigan Drive, Burlington, Vermont 05405, USA.
  5. Biochemistry Department, University of Nevada, 1664 North Virginia Street, Reno, Nevada 89557, USA.

Correspondence to: Elizabeth A Winzeler1,2 e-mail: winzeler@scripps.edu



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