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This natural product covalently bonds to the key immunological protein MR1 in the endoplasmic reticulum of antigen presenting cells (APCs), enabling MR1 refolding and trafficking to the cell surface, where it interacts with T cell receptors (TCRs) on mucosal associated invariant T lymphocytes (MAIT cells), activating their immunological and antimicrobial properties. Here, we strategically modify this natural product to understand the molecular basis of its recognition by MR1. This culminated in the discovery of new water\u2010stable compounds with extremely powerful and distinctive immunological functions. We report their capacity to bind MR1 inside APCs, triggering its expression on the cell surface (EC\n                    <jats:sub>50<\/jats:sub>\n                    17\u2005nM), and their potent activation (EC\n                    <jats:sub>50<\/jats:sub>\n                    56\u2005pM) or inhibition (IC\n                    <jats:sub>50<\/jats:sub>\n                    80\u2005nM) of interacting MAIT cells. We further derivatize compounds with diazirine\u2010alkyne, biotin, or fluorophore (Cy5 or AF647) labels for detecting, monitoring, and studying cellular MR1. Computer modeling casts new light on the molecular mechanism of activation, revealing that potent activators are first captured in a tyrosine\u2010 and serine\u2010lined cleft in MR1 via specific pi\u2010interactions and H\u2010bonds, before more tightly attaching via a covalent bond to Lys43 in MR1. This chemical study advances our molecular understanding of how bacterial metabolites are captured by MR1, influence cell surface expression of MR1, interact with T cells to induce immunity, and offers novel clues for developing new vaccine adjuvants, immunotherapeutics, and anticancer drugs.\n                  <\/jats:p>","DOI":"10.1002\/anie.202400632","type":"journal-article","created":{"date-parts":[[2024,4,29]],"date-time":"2024-04-29T00:34:40Z","timestamp":1714350880000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Potent Immunomodulators Developed from an Unstable Bacterial Metabolite of Vitamin B2 Biosynthesis"],"prefix":"10.1002","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8011-4539","authenticated-orcid":false,"given":"Jeffrey Y. W.","family":"Mak","sequence":"first","affiliation":[{"name":"Centre for Chemistry and Drug Discovery and ARC Centre of Excellence for Innovations in Peptide and Protein Science Institute for Molecular Bioscience The University of Queensland  Brisbane, Queensland 4072 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan J. D.","family":"Rivero","sequence":"additional","affiliation":[{"name":"Centre for Chemistry and Drug Discovery and ARC Centre of Excellence for Innovations in Peptide and Protein Science Institute for Molecular Bioscience The University of Queensland  Brisbane, Queensland 4072 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huy N.","family":"Hoang","sequence":"additional","affiliation":[{"name":"Centre for Chemistry and Drug Discovery and ARC Centre of Excellence for Innovations in Peptide and Protein Science Institute for Molecular Bioscience The University of Queensland  Brisbane, Queensland 4072 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin Yi","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity  Melbourne, Victoria 3000 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieru","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity  Melbourne, Victoria 3000 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamish E. G.","family":"McWilliam","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity  Melbourne, Victoria 3000 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose A.","family":"Villadangos","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity  Melbourne, Victoria 3000 Australia"},{"name":"Department of Biochemistry and Pharmacology Bio21 Molecular Science and Biotechnology Institute The University of Melbourne  Parkville, Victoria 3010 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"McCluskey","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity  Melbourne, Victoria 3000 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra J.","family":"Corbett","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity  Melbourne, Victoria 3000 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7856-8566","authenticated-orcid":false,"given":"David P.","family":"Fairlie","sequence":"additional","affiliation":[{"name":"Centre for Chemistry and Drug Discovery and ARC Centre of Excellence for Innovations in Peptide and Protein Science Institute for Molecular Bioscience The University of Queensland  Brisbane, Queensland 4072 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