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dc.contributor.authorGodoy-Ruiz, R.
dc.contributor.authorAdipietro, K.A.
dc.contributor.authorVarney, K.M.
dc.contributor.authorCook, M.E.
dc.contributor.authorRoth, B.M.
dc.contributor.authorWilder, P.T.
dc.contributor.authorNeu, H.M.
dc.contributor.authorMichel, S.L.J.
dc.contributor.authorPozharski, E.
dc.contributor.authorWeber, D.J.
dc.date.accessioned2020-02-04T17:04:32Z
dc.date.available2020-02-04T17:04:32Z
dc.date.issued2020
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85077937055&doi=10.1073%2fpnas.1919490117&partnerID=40&md5=61c42c042be1e17814ac736cd3c58da5
dc.identifier.urihttp://hdl.handle.net/10713/11676
dc.description.abstractTargeting Clostridium difficile infection is challenging because treatment options are limited, and high recurrence rates are common. One reason for this is that hypervirulent C. difficile strains often have a binary toxin termed the C. difficile toxin, in addition to the enterotoxins TsdA and TsdB. The C. difficile 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 (SymCDTb; 3.14 Å) and an asymmetric form (AsymCDTb; 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 AsymCDTb, a Ca2+ 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 C. difficile. Copyright 2020 the Author(s).en_US
dc.description.urihttps://doi.org/10.1073/pnas.1919490117en_US
dc.language.isoen_USen_US
dc.publisherNational Academy of Sciencesen_US
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of America
dc.subjectClostridium difficileen_US
dc.subjectcryo-EMen_US
dc.subjectNMRen_US
dc.subjectstructural biologyen_US
dc.subjectX-ray crystallographyen_US
dc.titleStructure of the cell-binding component of the Clostridium difficile binary toxin reveals a di-heptamer macromolecular assemblyen_US
dc.typeArticleen_US
dc.identifier.doi10.1073/pnas.1919490117
dc.identifier.pmid31896582


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