dc.contributor.author
Wiedemann, C.
dc.contributor.author
Whittaker, J. J.
dc.contributor.author
Pérez Carrillo, V. H.
dc.contributor.author
Goretzki, B.
dc.contributor.author
Dajka, Marina
dc.contributor.author
Tebbe, F.
dc.contributor.author
Harder, J. -M.
dc.contributor.author
Krajczy, P. R.
dc.contributor.author
Joseph, Benesh
dc.contributor.author
Hausch, F.
dc.date.accessioned
2024-01-19T07:01:00Z
dc.date.available
2024-01-19T07:01:00Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/42095
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-41820
dc.description.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.
en
dc.format.extent
15 Seiten
dc.rights.uri
https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject
Virulence factor
en
dc.subject
Protein inhibitor complex
en
dc.subject
Protein dynamics
en
dc.subject.ddc
500 Naturwissenschaften und Mathematik::570 Biowissenschaften; Biologie::570 Biowissenschaften; Biologie
dc.title
Legionella pneumophila macrophage infectivity potentiator protein appendage domains modulate protein dynamics and inhibitor binding
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.articlenumber
126366
dcterms.bibliographicCitation.doi
10.1016/j.ijbiomac.2023.126366
dcterms.bibliographicCitation.journaltitle
International Journal of Biological Macromolecules
dcterms.bibliographicCitation.volume
252
dcterms.bibliographicCitation.url
https://doi.org/10.1016/j.ijbiomac.2023.126366
refubium.affiliation
Physik
refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.isPartOf.eissn
1879-0003
refubium.resourceType.provider
WoS-Alert