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Macrophage infectivity potentiator (MIP) proteins are present in many microbial pathogens, both of pro- and of eukaryotic origin. MIP proteins play important roles in microbial virulence, facilitating processes like host cell infection, pathogen replication and dissemination. While their domain architecture differs in MIPs, they all share a FKBP (FK506 binding protein)-like prolyl-cis/trans-isomerase domain. Due to its high conservation, the FKBP domain has been a target for inhibitor development, including pipecolic acid derivatives. Here, we determined the high-resolution crystal structures of Burkholderia pseudomallei and Trypanosoma cruzi MIP in complex with fluorinated pipecolic acid inhibitors. Furthermore, we compared the inhibitor binding profiles of MIP proteins from B. pseudomallei, T. cruzi and Legionella pneumophila MIP using 1H, 15N-NMR spectroscopy. Additionally, 19F NMR was used to gauge inhibitor binding to the different MIP proteins. Complementary approaches including EPR spectroscopy and SAXS were used to investigate the global structural changes of homodimeric L. pneumophila MIP upon inhibitor binding. Our data provide a foundation for future inhibitor optimization and advance our understanding of the unexpected dynamic variability within a structurally conserved protein family.
Carrillo et al. (Fri,) studied this question.