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

Autor:	Gárdonyi M; Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 8, D-35037 Marburg, Germany., Hasewinkel C; Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 8, D-35037 Marburg, Germany., Wallbaum J; Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 8, D-35037 Marburg, Germany., Wollenhaupt J; Macromolecular Crystallography, Helmholtz-Zentrum Berlin, Albert-Einstein-Straße 15, D-12489 Berlin, Germany., Weiss MS; Macromolecular Crystallography, Helmholtz-Zentrum Berlin, Albert-Einstein-Straße 15, D-12489 Berlin, Germany., Klebe G; Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 8, D-35037 Marburg, Germany., Reuter K; Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 8, D-35037 Marburg, Germany., Heine A; Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 8, D-35037 Marburg, Germany.
Jazyk:	angličtina
Zdroj:	ACS omega [ACS Omega] 2023 Nov 20; Vol. 8 (48), pp. 46051-46065. Date of Electronic Publication: 2023 Nov 20 (Print Publication: 2023).
DOI:	10.1021/acsomega.3c07058
Abstrakt:	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. Competing Interests: The authors declare no competing financial interest. (© 2023 The Authors. Published by American Chemical Society.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu