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The newly discovered <jats:italic><jats:underline>C.<\/jats:underline><\/jats:italic><jats:italic>difficile<\/jats:italic><jats:underline>a<\/jats:underline>denine <jats:underline>m<\/jats:underline>ethyltransferase <jats:underline>A<\/jats:underline> (CamA) is specified by all <jats:italic>C. difficile<\/jats:italic> genomes sequenced to date (&gt;300), but is rare among other bacteria. CamA is an orphan methyltransferase, unassociated with a restriction endonuclease. CamA-mediated methylation at CAAAA<jats:underline>A<\/jats:underline> is required for normal sporulation, biofilm formation, and intestinal colonization by <jats:italic>C. difficile<\/jats:italic>. We characterized CamA kinetic parameters, and determined its structure bound to DNA containing the recognition sequence. CamA contains an N-terminal domain for catalyzing methyl transfer, and a C-terminal DNA recognition domain. Major and minor groove DNA contacts in the recognition site involve base-specific hydrogen bonds, van der Waals contacts and the Watson-Crick pairing of a rearranged A:T base pair. These provide sufficient sequence discrimination to ensure high specificity. Finally, the surprisingly weak binding of the methyl donor <jats:italic>S<\/jats:italic>-adenosyl-<jats:sc>l<\/jats:sc>-methionine (SAM) might provide avenues for inhibiting CamA activity using SAM analogs.<\/jats:p>","DOI":"10.1038\/s41467-021-23693-w","type":"journal-article","created":{"date-parts":[[2021,6,8]],"date-time":"2021-06-08T10:10:47Z","timestamp":1623147047000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Clostridioides difficile specific DNA adenine methyltransferase CamA squeezes and flips adenine out of DNA helix"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4104-7158","authenticated-orcid":false,"given":"Jujun","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9749-8068","authenticated-orcid":false,"given":"John R.","family":"Horton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert M.","family":"Blumenthal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6967-6362","authenticated-orcid":false,"given":"Xiaodong","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,6,8]]},"reference":[{"key":"23693_CR1","doi-asserted-by":"publisher","first-page":"16020","DOI":"10.1038\/nrdp.2016.20","volume":"2","author":"WK Smits","year":"2016","unstructured":"Smits, W. 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