TY  - INPR
A1  - Wiedemann, Christoph
A1  - Whittaker, Jacob J.
A1  - Pérez Carrillo, Victor Hugo
A1  - Goretzki, Benedikt
A1  - Dajka, Marina
A1  - Tebbe, Frederike
A1  - Harder, Jean-Martin
A1  - Krajczy, Patryk
A1  - Joseph, Benesh
A1  - Hausch, Felix
A1  - Guskov, Albert
A1  - Hellmich, Ute
T1  - Legionella pneumophila macrophage infectivity potentiator protein appendage domains modulate protein dynamics and inhibitor binding
T2  - bioRxiv
N2  - Macrophage infectivity potentiator (MIP) proteins are widespread in human pathogens including Legionella pneumophila, the causative agent of Legionnaires’ disease and protozoans such as Trypanosoma cruzi. All MIP proteins contain a FKBP (FK506 binding protein)-like prolyl-cis/trans- isomerase domain that hence presents an attractive drug target. Some MIPs such as the Legionella pneumophila protein (LpMIP) have additional appendage domains of mostly unknown function. In full- length, homodimeric LpMIP, the N-terminal dimerization domain is linked to the FKBP-like domain via a long, free-standing stalk helix. Combining X-ray crystallography, NMR and EPR spectroscopy and SAXS, we elucidated the importance of the stalk helix for protein dynamics and inhibitor binding to the FKBP-like domain and bidirectional crosstalk between the different protein regions. The first comparison of a microbial MIP and a human FKBP in complex with the same synthetic inhibitor was made possible by high-resolution structures of LpMIP with a [4.3.1]-aza-bicyclic sulfonamide and provides a basis for designing pathogen-selective inhibitors. Through stereospecific methylation, the affinity of inhibitors to L. pneumophila and T. cruzi MIP was greatly improved. The resulting X-ray inhibitor-complex structures of LpMIP and TcMIP at 1.49 and 1.34 Å, respectively, provide a starting point for developing potent inhibitors against MIPs from multiple pathogenic microorganisms.
Y1  - 2023
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/74959
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-749593
IS  - 2023.04.24.538046 Version 2
ER  -