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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,9,24]]},"abstract":"<jats:p>\n                    <jats:italic>Klebsiella pneumoniae<\/jats:italic>\n                    is an important pathogen causing difficult-to-treat urinary tract infections (UTIs). Over 1.5 million women per year suffer from recurrent UTI, reducing quality of life and causing substantial morbidity and mortality, especially in the hospital setting. Uropathogenic\n                    <jats:italic>E. coli<\/jats:italic>\n                    (UPEC) is the most prevalent cause of UTI. Like UPEC,\n                    <jats:italic>K. pneumoniae<\/jats:italic>\n                    relies on type 1 pili, tipped with the mannose-binding adhesin FimH, to cause cystitis. However,\n                    <jats:italic>K. pneumoniae<\/jats:italic>\n                    FimH is a poor binder of mannose, despite a mannose-binding pocket identical to UPEC FimH. FimH is composed of two domains that are in an equilibrium between tense (low-affinity) and relaxed (high-affinity) conformations. Substantial interdomain interactions in the tense conformation yield a low-affinity, deformed mannose-binding pocket, while domain\u2013domain interactions are broken in the relaxed state, resulting in a high-affinity binding pocket. Using crystallography, we identified the structural basis by which domain\u2013domain interactions direct the conformational equilibrium of\n                    <jats:italic>K. pneumoniae<\/jats:italic>\n                    FimH, which is strongly shifted toward the low-affinity tense state. Removal of the pilin domain restores mannose binding to the lectin domain, thus showing that poor mannose binding by\n                    <jats:italic>K. pneumoniae<\/jats:italic>\n                    FimH is not an inherent feature of the mannose-binding pocket. Phylogenetic analyses of\n                    <jats:italic>K. pneumoniae<\/jats:italic>\n                    genomes found that FimH sequences are highly conserved. However, we surveyed a collection of\n                    <jats:italic>K. pneumoniae<\/jats:italic>\n                    isolates from patients with long-term indwelling catheters and identified isolates that possessed relaxed higher-binding FimH variants, which increased\n                    <jats:italic>K. pneumoniae<\/jats:italic>\n                    fitness in bladder infection models, suggesting that long-term residence within the urinary tract may select for higher-binding FimH variants.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2409655121","type":"journal-article","created":{"date-parts":[[2024,9,17]],"date-time":"2024-09-17T13:40:03Z","timestamp":1726580403000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":27,"title":["Conformational ensembles in\n                    <i>Klebsiella pneumoniae<\/i>\n                    FimH impact uropathogenesis"],"prefix":"10.1073","volume":"121","author":[{"given":"Edward D. B.","family":"Lopatto","sequence":"first","affiliation":[{"name":"Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110"},{"name":"Center for Women\u2019s Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerome S.","family":"Pinkner","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110"},{"name":"Center for Women\u2019s Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6903-0273","authenticated-orcid":false,"given":"Denise A.","family":"Sanick","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110"},{"name":"Center 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Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin O.","family":"Tamadonfar","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110"},{"name":"Center for Women\u2019s Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijun","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110"},{"name":"Center for Women\u2019s Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxwell I.","family":"Zimmerman","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110"},{"name":"Center for Women\u2019s Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2697-5862","authenticated-orcid":false,"given":"Nathaniel C.","family":"Gualberto","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110"},{"name":"Center for Women\u2019s Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen W.","family":"Dodson","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110"},{"name":"Center for Women\u2019s Infectious Disease Research, Washington University School of 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