# Structure and Dynamics of Macrophage Infectivity Potentiator Proteins from Pathogenic Bacteria and Protozoans Bound to Fluorinated Pipecolic Acid Inhibitors

## TL;DR

Scientists studied how certain proteins from harmful bacteria and parasites interact with specific inhibitors, using advanced techniques to better understand how to design effective drugs.

## Contribution

The study provides high-resolution structural and dynamic insights into MIP-inhibitor interactions using a combination of NMR, EPR, and SAXS.

## Key findings

- Crystal structures of MIPs from B. pseudomallei and T. cruzi bound to fluorinated pipecolic acid inhibitors were determined.
- 19F NMR revealed differences in ligand binding dynamics across MIPs from different species.
- Inhibitor-induced structural changes in L. pneumophila MIP were observed using EPR and SAXS.

## 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.