Structure of the Toxoplasma gondii ROP18 kinase domain reveals a second ligand binding pocket required for acute virulence
| Autor: | Emily E. Rosowski, Lindsay Julien, Wendy Niedelman, Michael B. Yaffe, Daniel A. Gold, Jeroen P. J. Saeij, Daniel Lim |
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| Rok vydání: | 2013 |
| Předmět: |
Protein Conformation
Rhoptry Protein DNA Mutational Analysis Protozoan Proteins Crystallography X-Ray Ligands Biochemistry Medical and Health Sciences Protein Phosphorylation Toxoplasma Gondii Mice 2.1 Biological and endogenous factors 2.2 Factors relating to the physical environment Aetiology education.field_of_study Crystallography biology Biological Sciences Protein-Serine-Threonine Kinases Foodborne Illness Infectious Diseases Protozoan Crystal Structure Signal transduction Infection Toxoplasma Toxoplasmosis Protein Binding Signal Transduction Protein Structure Biochemistry & Molecular Biology Population Virulence Protein Serine-Threonine Kinases Microbiology Vaccine Related Biodefense parasitic diseases Genetics Animals Humans Binding site education Protein kinase A Molecular Biology Binding Sites Intracellular parasite Prevention Toxoplasma gondii Cell Biology biology.organism_classification Virology Protein Structure Tertiary Emerging Infectious Diseases Protein kinase domain Chemical Sciences X-Ray Protein Kinases Tertiary |
| Zdroj: | The Journal of biological chemistry, vol 288, iss 48 |
| Popis: | At least a third of the human population is infected with the intracellular parasite Toxoplasma gondii, which contributes significantly to the disease burden in immunocompromised and neutropenic hosts and causes serious congenital complications when vertically transmitted to the fetus. Genetic analyses have identified the Toxoplasma ROP18 Ser/Thr protein kinase as a major factor mediating acute virulence in mice. ROP18 is secreted into the host cell during the invasion process, and its catalytic activity is required for the acute virulence phenotype. However, its precise molecular function and regulation are not fully understood. We have determined the crystal structure of the ROP18 kinase domain, which is inconsistent with a previously proposed autoinhibitory mechanism of regulation. Furthermore, a sucrose molecule bound to our structure identifies an additional ligand-binding pocket outside of the active site cleft. Mutational analysis confirms an important role for this pocket in virulence. |
| Databáze: | OpenAIRE |
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