Crystallographic Fragment Screening on the Shigella Type III Secretion System Chaperone IpgC

The Shigella pathogenicity factor IpgC belongs to the class II of type III secretion system chaperones, whose members are characterized by a tetratricopeptide repeat (TPR) domain consisting of three and a half TPR motifs. Since IpgC is essential for Shigella virulence, we determined a high-resolu...

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Main Authors: Gárdonyi, Marina, Hasewinkel, Christian, Wallbaum, Johanna, Wollenhapt, Jan, Weiss, Manfred S., Klebe, Gerhard, Reuter, Klaus, Heine, Andreas
Format: Article
Language:English
Published: Philipps-Universität Marburg 2023
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Summary:The Shigella pathogenicity factor IpgC belongs to the class II of type III secretion system chaperones, whose members are characterized by a tetratricopeptide repeat (TPR) domain consisting of three and a half TPR motifs. Since IpgC is essential for Shigella virulence, we determined a high-resolution crystal structure of this chaperone to facilitate its use as a target for the structure-based design of anti-shigellosis compounds. The crystal structure revealed two possible homodimer assemblies, which strongly differ from the homodimer architectures so far known for IpgC and orthologues thereof. Through crystallographic fragment screening, we identified 10 small molecules that bind to IpgC and, therefore, are available for expansion to generate larger, more potent binders. A follow-up compound, based on one of our fragment hits, binds to a strictly conserved site, which overlaps with the binding site of the chaperone’s substrates, IpaB and IpaC. Therefore, it constitutes a promising starting point for the design of functional IpgC inhibitors.
Item Description:Gefördert durch den Open-Access-Publikationsfonds der UB Marburg.
DOI:10.1021/acsomega.3c07058