{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:14:55Z","timestamp":1782864895863,"version":"3.54.5"},"reference-count":58,"publisher":"National Academy of Sciences","issue":"47","license":[{"start":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T00:00:00Z","timestamp":1731369600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"National Academic Infrastructure for Supercomputing in Sweden","award":["NAISS 2023\/1-31"],"award-info":[{"award-number":["NAISS 2023\/1-31"]}]},{"DOI":"10.13039\/501100004063","name":"Knut och Alice Wallenbergs Stiftelse","doi-asserted-by":"publisher","award":["KAW 2019.0043"],"award-info":[{"award-number":["KAW 2019.0043"]}],"id":[{"id":"10.13039\/501100004063","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,11,19]]},"abstract":"<jats:p>\n                    Tuberculosis is one of the most common causes of death worldwide, with a rapid emergence of multi-drug-resistant strains underscoring the need for new antituberculosis drugs. Recent studies indicate that lansoprazole\u2014a known gastric proton pump inhibitor and its intracellular metabolite, lansoprazole sulfide (LPZS)\u2014are potential antituberculosis compounds. Yet, their inhibitory mechanism and site of action still remain unknown. Here, we combine biochemical, computational, and structural approaches to probe the interaction of LPZS with the respiratory chain supercomplex III\n                    <jats:sub>2<\/jats:sub>\n                    IV\n                    <jats:sub>2<\/jats:sub>\n                    of\n                    <jats:italic>Mycobacterium smegmatis<\/jats:italic>\n                    , a close homolog of\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    supercomplex. We show that LPZS binds to the Q\n                    <jats:sub>o<\/jats:sub>\n                    cavity of the mycobacterial supercomplex, inhibiting the quinol substrate oxidation process and the activity of the enzyme. We solve high-resolution (2.6 \u00c5) cryo-electron microscopy (cryo-EM) structures of the supercomplex with bound LPZS that together with microsecond molecular dynamics simulations, directed mutagenesis, and functional assays reveal key interactions that stabilize the inhibitor, but also how mutations can lead to the emergence of drug resistance. Our combined findings reveal an inhibitory mechanism of LPZS and provide a structural basis for drug development against tuberculosis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2412780121","type":"journal-article","created":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T13:40:11Z","timestamp":1731418811000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":4,"title":["Inhibition mechanism of potential antituberculosis compound lansoprazole sulfide"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0144-2463","authenticated-orcid":false,"given":"Terezia","family":"Kovalova","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Biophysics, The Arrhenius Laboratories for Natural Sciences, Stockholm University, 106 91 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylwia","family":"Kr\u00f3l","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, The Arrhenius Laboratories for Natural Sciences, Stockholm University, 106 91 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0961-328X","authenticated-orcid":false,"given":"Ana P.","family":"Gamiz-Hernandez","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, The Arrhenius Laboratories for Natural Sciences, Stockholm University, 106 91 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Sj\u00f6strand","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, The Arrhenius Laboratories for Natural Sciences, Stockholm University, 106 91 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4464-6324","authenticated-orcid":false,"given":"Ville R. 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