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Crystal structure of Mip, a prolylisomerase from Legionella pneumophila
A Riboldi-Tunnicliffe1, B König, S Jessen
1Institute of Molecular Biotechnology, Beutenbergstr. 11, D-07745 Jena, Germany.
Abstract:
The human pathogen Legionella pneumophila, the etiological agent of the severe and often fatal Legionnaires' disease, produces a major virulence factor, termed 'macrophage infectivity potentiator protein' (Mip), that is necessary for optimal multiplication of the bacteria within human alveolar macrophages. Mip exhibits a peptidyl prolyl cis-trans isomerase (PPIase) activity, which appears to be important for infection. Here we report the 2.4 A crystal structure of the Mip protein from L. pneumophila Philadelphia 1 and the 3.2 A crystal structure of its complex with the drug FK506. Each monomer of the homodimeric protein consists of an N-terminal dimerization module, a long (65 A) connecting alpha-helix and a C-terminal PPIase domain exhibiting similarity to human FK506-binding protein. In view of the recent significant increase in the number of reported cases of Legionnaires' disease and other intracellular infections, these structural results are of prime interest for the design of new drugs directed against Mip proteins of intracellular pathogens.
Insights
Legionnaires
Area of Science:
- Structural biology
- Microbiology
- Drug discovery
Background:
- Legionella pneumophila causes Legionnaires' disease, a severe respiratory infection.
- The macrophage infectivity potentiator protein (Mip) is crucial for L. pneumophila virulence.
- Mip possesses peptidyl prolyl cis-trans isomerase (PPIase) activity essential for bacterial multiplication in macrophages.
Purpose of the Study:
- To determine the crystal structure of the L. pneumophila Mip protein.
- To elucidate the structural basis of Mip's interaction with the drug FK506.
- To provide insights for developing novel therapeutics against intracellular pathogens.
Main Methods:
- X-ray crystallography was used to determine the 3D structure of the Mip protein.
- The crystal structure of the Mip-FK506 complex was also determined.
- Structural analysis focused on the homodimeric protein's domains and their arrangement.
Main Results:
- The crystal structure of the L. pneumophila Mip protein was resolved at 2.4 A resolution.
- The 3.2 A crystal structure of the Mip-FK506 complex revealed drug-protein interactions.
- The Mip monomer comprises an N-terminal dimerization module, a connecting alpha-helix, and a C-terminal PPIase domain similar to human FKBP.
Conclusions:
- The determined structures provide a detailed molecular understanding of the Mip protein.
- These findings are significant for designing targeted drugs against Mip in intracellular pathogens.
- The structural data can guide the development of new treatments for Legionnaires' disease and related infections.