Solution structure of the Legionella pneumophila Mip-rapamycin complex.
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.


CONCLUSIONS
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.
Ceymann
Andreas
A
Department of Experimental Physics 5, University of Würzburg, Würzburg, Germany. asceyman@physik.uni-wuerzburg.de
Horstmann
Martin
M
Ehses
Philipp
P
Schweimer
Kristian
K
Paschke
Anne-Katrin
AK
Steinert
Michael
M
Faber
Cornelius
C
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D016952:Legionella pneumophila / Q000201:enzymology* / Q000378:metabolism; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019696:Peptidylprolyl Isomerase / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D020123:Sirolimus / Q000737:chemistry* / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000737:chemistry / Q000378:metabolism
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D008024:Ligands; D022021:Tacrolimus Binding Proteins; C512922:Mip protein, Legionella pneumophila; D019696:Peptidylprolyl Isomerase; D020123:Sirolimus