Unknown

Dataset Information

0

Toxoplasma gondii calcium-dependent protein kinase 1 is a target for selective kinase inhibitors.

ABSTRACT: New drugs are needed to treat toxoplasmosis. Toxoplasma gondii calcium-dependent protein kinases (TgCDPKs) are attractive targets because they are absent in mammals. We show that TgCDPK1 is inhibited by low nanomolar levels of bumped kinase inhibitors (BKIs), compounds inactive against mammalian kinases. Cocrystal structures of TgCDPK1 with BKIs confirm that the structural basis for selectivity is due to the unique glycine gatekeeper residue in the ATP-binding site. We show that BKIs interfere with an early step in T. gondii infection of human cells in culture. Furthermore, we show that TgCDPK1 is the in vivo target of BKIs because T. gondii expressing a glycine to methionine gatekeeper mutant enzyme show significantly decreased sensitivity to BKIs. Thus, design of selective TgCDPK1 inhibitors with low host toxicity may be achievable.

SUBMITTER: Ojo KK 

PROVIDER: S-EPMC2896873 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

Json Xml
altmetric image

Publications

New drugs are needed to treat toxoplasmosis. Toxoplasma gondii calcium-dependent protein kinases (TgCDPKs) are attractive targets because they are absent in mammals. We show that TgCDPK1 is inhibited by low nanomolar levels of bumped kinase inhibitors (BKIs), compounds inactive against mammalian kinases. Cocrystal structures of TgCDPK1 with BKIs confirm that the structural basis for selectivity is due to the unique glycine gatekeeper residue in the ATP-binding site. We show that BKIs interfere w  ...[more]

Similar Datasets

Unknown Development of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) inhibitors with potent anti-toxoplasma activity.
| S-EPMC3306180 | biostudies-literature
Unknown Bioinformatics analysis of calcium-dependent protein kinase 4 (CDPK4) as Toxoplasma gondii vaccine target.
| S-EPMC7865105 | biostudies-literature
Unknown The calcium-dependent protein kinase 1 from Toxoplasma gondii as target for structure-based drug design.
| S-EPMC5964469 | biostudies-literature
Unknown Characterization of a Toxoplasma gondii calcium calmodulin-dependent protein kinase homolog.
| S-EPMC4957278 | biostudies-literature
Unknown Optimizing small molecule inhibitors of calcium-dependent protein kinase 1 to prevent infection by Toxoplasma gondii.
| S-EPMC3625458 | biostudies-literature
Unknown Discovery of Potent and Selective Inhibitors of Calcium-Dependent Protein Kinase 1 (CDPK1) from C. parvum and T. gondii.
| S-EPMC2992447 | biostudies-literature
Unknown Characterisation of the Toxoplasma gondii tyrosine transporter and its phosphorylation by the calcium-dependent protein kinase 3.
| S-EPMC6488386 | biostudies-literature
Unknown Artemisinin induces calcium-dependent protein secretion in the protozoan parasite Toxoplasma gondii.
| S-EPMC2168421 | biostudies-literature
Unknown Genome-wide expression patterns of calcium-dependent protein kinases in Toxoplasma gondii.
| S-EPMC4459671 | biostudies-literature
Unknown Evaluation of immune responses in mice after DNA immunization with putative Toxoplasma gondii calcium-dependent protein kinase 5.
| S-EPMC4097438 | biostudies-literature