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Publication Abstract from PubMed

Contact-dependent growth inhibition (CDI) is a widespread mechanism of inter-bacterial competition mediated by the CdiB/CdiA family of two-partner secretion proteins. CdiA effectors carry diverse C-terminal toxin domains (CdiA-CT), which are delivered into neighboring target cells to inhibit growth. CDI(+) bacteria also produce CdiI immunity proteins that bind specifically to cognate CdiA-CT toxins and protect the cell from auto-inhibition. Here, we compare the structures of homologous CdiA-CT/CdiI complexes from Escherichia coli EC869 and Yersinia pseudotuberculosis YPIII to explore the evolution of CDI toxin/immunity protein interactions. Both complexes share an unusual beta-augmentation interaction, in which the toxin domain extends a beta-hairpin into the immunity protein to complete a six-stranded anti-parallel sheet. However, the specific contacts differ substantially between the two complexes. The EC869 beta-hairpin interacts mainly through direct H-bond and ion-pair interactions, whereas the YPIII beta-hairpin pocket contains more hydrophobic contacts and a network of bridging water molecules. In accord with these differences, we find that each CdiI protein only protects target bacteria from its cognate CdiA-CT toxin. The compact beta-hairpin binding pocket within the immunity protein represents a tractable system for the rationale design of small molecules to block CdiA-CT/CdiI complex formation. We synthesized a macrocyclic peptide mimic of the beta-hairpin from EC869 toxin and solved its structure in complex with cognate immunity protein. These latter studies suggest that small molecules could potentially be used to disrupt CDI toxin/immunity complexes.

Diversification of beta-Augmentation Interactions between CDI Toxin/Immunity Proteins.,Morse RP, Willett JL, Johnson PM, Zheng J, Credali A, Iniguez A, Nowick JS, Hayes CS, Goulding CW J Mol Biol. 2015 Nov 20;427(23):3766-84. doi: 10.1016/j.jmb.2015.09.020. Epub, 2015 Oct 9. PMID:26449640^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.