Article ; Online: Legionella pneumophila macrophage infectivity potentiator protein appendage domains modulate protein dynamics and inhibitor binding.
International journal of biological macromolecules
2023 Volume 252, Page(s) 126366
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 ... ...
| 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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| MeSH term(s) | Humans ; Legionella pneumophila/metabolism ; Scattering, Small Angle ; X-Ray Diffraction ; Bacterial Proteins/chemistry ; Tacrolimus Binding Proteins/chemistry ; Legionnaires' Disease ; Macrophages/metabolism |
| Chemical Substances | Bacterial Proteins ; Tacrolimus Binding Proteins (EC 5.2.1.-) |
| Language | English |
| Publishing date | 2023-08-24 |
| Publishing country | Netherlands |
| Document type | Journal Article |
| ZDB-ID | 282732-3 |
| ISSN | 1879-0003 ; 0141-8130 |
| ISSN (online) | 1879-0003 |
| ISSN | 0141-8130 |
| DOI | 10.1016/j.ijbiomac.2023.126366 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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