8BK6
A truncated structure of LpMIP with bound inhibitor JK095.
Summary for 8BK6
| Entry DOI | 10.2210/pdb8bk6/pdb |
| Descriptor | Peptidyl-prolyl cis-trans isomerase, DI(HYDROXYETHYL)ETHER, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (4 entities in total) |
| Functional Keywords | macrophage, potentiator, soluble, protein., structural protein |
| Biological source | Legionella pneumophila |
| Total number of polymer chains | 2 |
| Total formula weight | 24504.99 |
| Authors | Whittaker, J.J.,Guskov, A.,Hellmich, A.U.,Goretzki, B. (deposition date: 2022-11-08, release date: 2023-09-06, Last modification date: 2023-09-13) |
| Primary citation | Wiedemann, C.,Whittaker, J.J.,Perez Carrillo, V.H.,Goretzki, B.,Dajka, M.,Tebbe, F.,Harder, J.M.,Krajczy, P.R.,Joseph, B.,Hausch, F.,Guskov, A.,Hellmich, U.A. Legionella pneumophila macrophage infectivity potentiator protein appendage domains modulate protein dynamics and inhibitor binding. Int.J.Biol.Macromol., 252:126366-126366, 2023 Cited by PubMed 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. PubMed: 37633566DOI: 10.1016/j.ijbiomac.2023.126366 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.263 Å) |
Structure validation
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