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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...
Gorde:
| Egile Nagusiak: | , , , , , , , |
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| Formatua: | Artikulua |
| Hizkuntza: | ingelesa |
| Argitaratua: |
Philipps-Universität Marburg
2023
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| Gaiak: | |
| Sarrera elektronikoa: | PDF testu osoa |
| Etiketak: |
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| Gaia: | 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. |
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| Alearen deskribapena: | Gefördert durch den Open-Access-Publikationsfonds der UB Marburg. |
| DOI: | 10.1021/acsomega.3c07058 |