Related Experiment Video

Updated: Jun 13, 2026

Understanding the Development of Compensatory Pathways in a Mutant Malaria Parasite Harbouring Hypomorphic Allele of Plant-Like Kinases
09:13

Understanding the Development of Compensatory Pathways in a Mutant Malaria Parasite Harbouring Hypomorphic Allele of Plant-Like Kinases

Published on: November 22, 2024

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

Kayode K Ojo1, Eric T Larson, Katelyn R Keyloun

  • 1Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington, USA.

Nature Structural & Molecular Biology
|May 4, 2010
PubMed

Insights

New bumped kinase inhibitors (BKIs) effectively target Toxoplasma gondii calcium-dependent protein kinases (TgCDPKs), crucial for parasite survival. These BKIs offer a promising avenue for developing selective anti-toxoplasmosis drugs with minimal host toxicity.

Area of Science:

  • Parasitology
  • Drug Discovery
  • Structural Biology

Background:

  • Toxoplasmosis treatment options are limited.
  • Toxoplasma gondii calcium-dependent protein kinases (TgCDPKs) are essential for parasite survival and absent in humans, making them ideal drug targets.

Purpose of the Study:

  • To identify and characterize inhibitors of TgCDPK1.
  • To elucidate the structural basis for selective inhibition of TgCDPK1.
  • To evaluate the efficacy of inhibitors against T. gondii infection.

Main Methods:

  • Biochemical assays to test kinase inhibition.
  • Cocrystallography to determine inhibitor-bound enzyme structures.
  • Cell-based assays to assess inhibition of T. gondii infection.
  • Genetic modification of T. gondii to create resistant strains.

Main Results:

  • Bumped kinase inhibitors (BKIs) potently inhibit TgCDPK1 at nanomolar concentrations.
  • Cocrystal structures reveal selective binding of BKIs due to TgCDPK1's unique glycine gatekeeper residue.
  • BKIs block an early stage of T. gondii infection in human cells.
  • Mutating the glycine gatekeeper to methionine confers resistance to BKIs, confirming TgCDPK1 as the in vivo target.

Conclusions:

  • Selective TgCDPK1 inhibitors can be designed based on structural insights.
  • BKIs represent a promising class of compounds for treating toxoplasmosis.
  • Further development may lead to drugs with low host toxicity.

More Related Videos

Forward Genetics Screens Using Macrophages to Identify Toxoplasma gondii Genes Important for Resistance to IFN-γ-Dependent Cell Autonomous Immunity11:21

Forward Genetics Screens Using Macrophages to Identify Toxoplasma gondii Genes Important for Resistance to IFN-γ-Dependent Cell Autonomous Immunity

Published on: March 12, 2015

Genetic Manipulation in Δku80 Strains for Functional Genomic Analysis of Toxoplasma gondii09:52

Genetic Manipulation in Δku80 Strains for Functional Genomic Analysis of Toxoplasma gondii

Published on: July 12, 2013

Related Concept Videos

Toxoplasmosis01:28

Toxoplasmosis

Toxoplasmosis, a zoonotic disease caused by the protozoan Toxoplasma gondii, poses significant public health challenges globally due to its high seroprevalence and varied clinical manifestations. As an obligate intracellular parasite, T. gondii can infect all warm-blooded vertebrates, but felids are its only definitive hosts, shedding unsporulated oocysts into the environment. Humans typically acquire the infection through ingestion of tissue cysts in undercooked meat or oocysts from...
Protein Kinases and Phosphatases02:54

Protein Kinases and Phosphatases

Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
Protein Kinases and Phosphatases02:54

Protein Kinases and Phosphatases

Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against specific...
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
Transducer Mechanism: Enzyme-Linked Receptors01:27

Transducer Mechanism: Enzyme-Linked Receptors

Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include: