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TLR dimerization and recruitment of adapter molecules is critical for intracellular signaling and is mediated through intracellular Toll-Interleukin 1 Receptor Resistance (TIR) domain interactions. Human TIR domains, including reported structures of TIR1, TIR2, TIR6, TIR10, TIRAP, and MyD88, contain Cysteine (Cys) interactions or modifications that are disproportionally at, or near, reported biological TIR interfaces, or in close proximity to functionally important regions. Therefore, we hypothesized that intracellular TIR Cys regulation may have greater functional importance than previously appreciated. Expression of mutant TLR4-C747S or treatment of TLR4 reporter cells with a small molecule, Cys-binding inhibitor of TLR4, TAK-242, abrogated LPS signaling in vitro. Using TAK-242, mice were protected from lethal influenza challenge as previously reported for extracellular TLR4 antagonists. Molecular modeling and sequence analysis of the region surrounding TLR4-Cys747 indicate conservation of a WxxxE motif identified among bacterial and NAD\n                    <jats:sup>+<\/jats:sup>\n                    -consuming TIRs, as well as within the TIRs domains of surface TLRs 1, 2, 4, 6, and 10. Together, these data support the hypothesis that critical Cys within the TIR domain are essential for TLR4 functionality.\n                  <\/jats:p>","DOI":"10.1177\/1753425919846281","type":"journal-article","created":{"date-parts":[[2020,1,19]],"date-time":"2020-01-19T23:33:25Z","timestamp":1579476805000},"page":"26-34","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":14,"title":["Select targeting of intracellular Toll-interleukin-1 receptor resistance domains for protection against influenza-induced disease"],"prefix":"10.1177","volume":"26","author":[{"given":"Kari Ann","family":"Shirey","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Maryland School of Medicine, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wendy","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Maryland School of Medicine, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lindsey J","family":"Brown","sequence":"additional","affiliation":[{"name":"Institute of Human Virology, Department of Medicine, University of Maryland School of Medicine, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jorge C G","family":"Blanco","sequence":"additional","affiliation":[{"name":"Sigmovir Biosystems, Rockville, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Beadenkopf","sequence":"additional","affiliation":[{"name":"Institute of Human Virology, Department of Medicine, University of Maryland School of Medicine, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yajing","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Human Virology, Department of Medicine, University of Maryland School of Medicine, USA"},{"name":"China Pharmaceutical University, Nanjing, P.R. China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefanie N","family":"Vogel","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Maryland School of Medicine, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4409-0453","authenticated-orcid":false,"given":"Greg A","family":"Snyder","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Maryland School of Medicine, USA"},{"name":"Institute of Human Virology, Department of Medicine, University of Maryland School of Medicine, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2020,1,19]]},"reference":[{"key":"bibr1-1753425919846281","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.02.015"},{"key":"bibr2-1753425919846281","doi-asserted-by":"publisher","DOI":"10.1038\/nri3713"},{"key":"bibr3-1753425919846281","doi-asserted-by":"publisher","DOI":"10.2174\/13816128113199990069"},{"key":"bibr4-1753425919846281","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.177.1.322"},{"key":"bibr5-1753425919846281","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20084"},{"key":"bibr6-1753425919846281","unstructured":"Schr\u00f6dinger LLC. 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