Journal Article

PUBDB-2024-00357

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Legionella pneumophila macrophage infectivity potentiator protein appendage domains modulate protein dynamics and inhibitor binding

Wiedemann, C.Extern*EMBL* ; Whittaker, J. J.Extern*EMBL* ; Pérez Carrillo, V. H. ; Goretzki, B.Extern*EMBL* ; Dajka, M. ; Tebbe, F. ; Harder, J.-M. ; Krajczy, P. R. ; Joseph, B. ; Hausch, F.Extern*EMBL* ; Guskov, A.Extern*EMBL* ; Hellmich, U. (Corresponding author)Extern*EMBL*

2023
Elsevier New York, NY [u.a.]

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Please use a persistent id in citations: doi:10.1016/j.ijbiomac.2023.126366  doi:10.3204/PUBDB-2024-00357

Abstract: 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.

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Contributing Institute(s):

1. DOOR-User (DOOR ; HAS-User)
2. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)
2. DFG project 390713860 - EXC 2051: Balance of the Microverse (390713860) (390713860)

Experiment(s):

1. PETRA Beamline P12 (PETRA III)

Appears in the scientific report 2023

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Database coverage:
; ; ; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Web of Science Core Collection

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