Cryo-EM structures of the translocational binary toxin complex CDTa-bound CDTb-pore from Clostridioides difficile

Akihiro Kawamoto, Tomohito Yamada, Toru Yoshida, Yusui Sato, Takayuki Kato and Hideaki Tsuge ()
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Akihiro Kawamoto: Osaka University
Tomohito Yamada: Kyoto Sangyo University, Kamigamo-motoyama, Kita-ku
Toru Yoshida: Kyoto Sangyo University, Kamigamo-motoyama, Kita-ku
Yusui Sato: Analytical Instruments R&D Division, HORIBA, Ltd.
Takayuki Kato: Osaka University
Hideaki Tsuge: Kyoto Sangyo University, Kamigamo-motoyama, Kita-ku

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract Some bacteria express a binary toxin translocation system, consisting of an enzymatic subunit and translocation pore, that delivers enzymes into host cells through endocytosis. The most clinically important bacterium with such a system is Clostridioides difficile (formerly Clostridium). The CDTa and CDTb proteins from its system represent important therapeutic targets. CDTb has been proposed to be a di-heptamer, but its physiological heptameric structure has not yet been reported. Here, we report the cryo-EM structure of CDTa bound to the CDTb-pore, which reveals that CDTa binding induces partial unfolding and tilting of the first CDTa α-helix. In the CDTb-pore, an NSS-loop exists in ‘in’ and ‘out’ conformations, suggesting its involvement in substrate translocation. Finally, 3D variability analysis revealed CDTa movements from a folded to an unfolded state. These dynamic structural information provide insights into drug design against hypervirulent C. difficile strains.

Date: 2022
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DOI: 10.1038/s41467-022-33888-4

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