Structure of the cell-binding component of the binary toxin reveals a di-heptamer macromolecular assembly.

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TitleStructure of the cell-binding component of the binary toxin reveals a di-heptamer macromolecular assembly.
Publication TypeJournal Article
Year of Publication2020
AuthorsXu, X, Godoy-Ruiz, R, Adipietro, KA, Peralta, C, Ben-Hail, D, Varney, KM, Cook, ME, Roth, BM, Wilder, PT, Cleveland, T, Grishaev, A, Neu, HM, Michel, SLJ, Yu, W, Beckett, D, Rustandi, RR, Lancaster, C, Loughney, JW, Kristopeit, A, Christanti, S, Olson, JW, Mackerell, AD, Georges, Ades, Pozharski, E, Weber, DJ
JournalProc Natl Acad Sci U S A
Date Published2020 Jan 02
ISSN1091-6490
Abstract

Targeting infection is challenging because treatment options are limited, and high recurrence rates are common. One reason for this is that hypervirulent strains often have a binary toxin termed the toxin, in addition to the enterotoxins TsdA and TsdB. The toxin has an enzymatic component, termed CDTa, and a pore-forming or delivery subunit termed CDTb. CDTb was characterized here using a combination of single-particle cryoelectron microscopy, X-ray crystallography, NMR, and other biophysical methods. In the absence of CDTa, 2 di-heptamer structures for activated CDTb (1.0 MDa) were solved at atomic resolution, including a symmetric (CDTb; 3.14 Å) and an asymmetric form (CDTb; 2.84 Å). Roles played by 2 receptor-binding domains of activated CDTb were of particular interest since the receptor-binding domain 1 lacks sequence homology to any other known toxin, and the receptor-binding domain 2 is completely absent in other well-studied heptameric toxins (i.e., anthrax). For CDTb, a Ca binding site was discovered in the first receptor-binding domain that is important for its stability, and the second receptor-binding domain was found to be critical for host cell toxicity and the di-heptamer fold for both forms of activated CDTb. Together, these studies represent a starting point for developing structure-based drug-design strategies to target the most severe strains of .

DOI10.1073/pnas.1919490117
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID31896582