Solution structure of the Legionella pneumophila Mip-rapamycin complex

Area of Science:

• Structural biology
• Biochemistry
• Microbiology

Background:

• Legionella pneumophila causes Legionnaires' disease.
• The Mip protein is a key virulence factor with peptidyl-prolyl cis/trans isomerase activity.
• Mip binds FK506 and rapamycin, which inhibit its function.

Purpose of the Study:

• To determine the solution structure of Mip77-213 and its complex with rapamycin.
• To understand the binding mechanism of rapamycin to Mip.
• To inform the design of novel Mip inhibitors for treating Legionnaires' disease.

Main Methods:

• Nuclear Magnetic Resonance (NMR) spectroscopy was used to solve the solution structure.
• Comparison with existing FKBP12-rapamycin complex structures.

Main Results:

• The solution structure of Mip77-213 and its rapamycin complex were determined.
• Mip exhibits a typical FKBP-fold with minor rearrangements upon rapamycin binding.
• The binding mode of rapamycin to Mip is similar to that observed in FKBP12.

Conclusions:

• Structural similarity between Mip-rapamycin and FKBP12-rapamycin complexes suggests FKBP12 ligands as starting points for Mip inhibitor design.
• Known FKBP12 inhibitors can guide the development of new drugs against Legionnaires' disease.