Journal Article

PUBDB-2025-01421

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Structure and Dynamics of Macrophage Infectivity Potentiator Proteins from Pathogenic Bacteria and Protozoans Bound to Fluorinated Pipecolic Acid Inhibitors

Pérez Carrillo, V. H. ; Whittaker, J. J. ; Wiedemann, C. ; Harder, J.-M. ; Lohr, T. ; Jamithireddy, A. K. ; Dajka, M. ; Goretzki, B. ; Joseph, B. ; Guskov, A. ; Harmer, N. J. ; Holzgrabe, U. ; Hellmich, U. (Corresponding author)Extern*EMBL*

2025
ACS Washington, DC

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Please use a persistent id in citations: doi:10.1021/acs.jmedchem.5c00134  doi:10.3204/PUBDB-2025-01421

Abstract: Macrophage infectivity potentiator (MIP) proteins, found in pro- and eukaryotic pathogens, influence microbial virulence, host cell infection, pathogen replication, and dissemination. MIPs share an FKBP (FK506 binding protein)-like prolyl-cis/trans-isomerase domain, making them attractive targets for inhibitor development. We determined high-resolution crystal structures of Burkholderia pseudomallei and Trypanosoma cruzi MIPs in complex with fluorinated pipecolic acid inhibitors. The inhibitor binding profiles in solution were compared across B. pseudomallei, T. cruzi, and Legionella pneumophila MIPs using 1H, 15N, and 19F NMR spectroscopy. Demonstrating the versatility of fluorinated ligands for characterizing inhibitor complexes, 19F NMR spectroscopy identified differences in ligand binding dynamics across MIPs. EPR spectroscopy and SAXS further revealed inhibitor-induced global structural changes in homodimeric L. pneumophila MIP. This study demonstrates the importance of integrating diverse methods to probe protein dynamics and provides a foundation for optimizing MIP-targeted inhibitors in this structurally conserved yet dynamically variable protein family.

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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)
2. DFG project G:(GEPRIS)390713860 - EXC 2051: Balance of the Microverse (390713860) (390713860)
3. DFG project G:(GEPRIS)316213987 - SFB 1278: Polymerbasierte Nanopartikel-Bibliotheken für die Entwicklung zielgerichteter anti-inflammatorischer Strategien (316213987) (316213987)

Experiment(s):

1. PETRA Beamline P12 (PETRA III)

Appears in the scientific report 2025

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Database coverage:
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