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Crystallographic Fragment Screening on the Shigella Type III Secretion System Chaperone IpgC
Marina Gárdonyi1, Christian Hasewinkel1, Johanna Wallbaum1
1Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 8, D-35037 Marburg, Germany.
ACS Omega
|December 11, 2023
Summary
Researchers determined the crystal structure of the Shigella pathogenicity factor IpgC, a type III secretion system chaperone. This structure reveals new homodimer assemblies and identifies potential drug targets for anti-shigellosis compounds.
Area of Science:
- Microbiology
- Structural Biology
- Drug Discovery
Background:
- IpgC is a crucial type III secretion system chaperone essential for Shigella virulence.
- Class II chaperones, including IpgC, feature a tetratricopeptide repeat (TPR) domain.
Purpose of the Study:
- To determine the high-resolution crystal structure of IpgC.
- To identify potential drug targets for developing anti-shigellosis compounds.
- To understand IpgC homodimerization and substrate binding.
Main Methods:
- High-resolution crystal structure determination of IpgC.
- Crystallographic fragment screening.
- Structure-based drug design principles.
Main Results:
- Revealed two novel homodimer assemblies of IpgC, differing from known architectures.
- Identified 10 small molecules that bind to IpgC via fragment screening.
- Developed a follow-up compound binding to a conserved site overlapping with IpaB/IpaC substrate binding.
Conclusions:
- The determined IpgC structure provides a basis for structure-based drug design.
- The identified binding site is a promising starting point for developing functional IpgC inhibitors.
- This research facilitates the design of novel anti-shigellosis therapeutics.
