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