Solution structure of the Legionella pneumophila Mip-rapamycin complex

Springer Science and Business Media LLC - 2008
A. Ceymann1, Martin Horstmann1, Philipp Ehses1, Kristian Schweimer2, Anne-Katrin Paschke3, Michael Steinert4, Cornelius Faber1
1Department of Experimental Physics 5, University of Würzburg, Würzburg, Germany
2Department of Biopolymers, University of Bayreuth, Bayreuth, Germany
3Max Planck Research Unit "Enzymology of Protein Folding", Halle, Germany
4Institute for Molecular Biology of Infections, University of Würzburg, Würzburg, Germany

Tóm tắt

Abstract Background Legionella pneumphila is the causative agent of Legionnaires' disease. A major virulence factor of the pathogen is the homodimeric surface protein Mip. It shows peptidyl-prolyl cis/trans isomerase activty and is a receptor of FK506 and rapamycin, which both inhibit its enzymatic function. Insight into the binding process may be used for the design of novel Mip inhibitors as potential drugs against Legionnaires' disease. Results We have solved the solution structure of free Mip77–213 and the Mip77–213-rapamycin complex by NMR spectroscopy. Mip77–213 showed the typical FKBP-fold and only minor rearrangements upon binding of rapamycin. Apart from the configuration of a flexible hairpin loop, which is partly stabilized upon binding, the solution structure confirms the crystal structure. Comparisons to the structures of free FKBP12 and the FKBP12-rapamycin complex suggested an identical binding mode for both proteins. Conclusion The structural similarity of the Mip-rapamycin and FKBP12-rapamycin complexes suggests that FKBP12 ligands may be promising starting points for the design of novel Mip inhibitors. The search for a novel drug against Legionnaires' disease may therefore benefit from the large variety of known FKBP12 inhibitors.

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