{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T04:01:19Z","timestamp":1785902479597,"version":"3.56.0"},"reference-count":37,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T00:00:00Z","timestamp":1766448000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T00:00:00Z","timestamp":1766448000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Protein Science"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    (\n                    <jats:italic>Mtb<\/jats:italic>\n                    ), the causative agent of tuberculosis (TB), is responsible for a global health burden affecting over a quarter of the world's population. The increasing prevalence of drug\u2010resistant TB poses a significant threat to current treatment strategies. Isoniazid (INH) is a first\u2010line prodrug used in TB therapy, which requires activation by the catalase\u2010peroxidase enzyme KatG. Upon activation, INH inhibits InhA, thereby disrupting mycolic acid biosynthesis, a crucial process for maintaining\n                    <jats:italic>Mtb<\/jats:italic>\n                    's distinctive, lipid\u2010rich cell wall. The most common naturally occurring resistance\u2010associated mutation in KatG is S315T, though other variants at this position, such as S315G, S315N, S315I, and S315R, have also been reported. In this study, we employ cryo\u2010electron microscopy (cryo\u2010EM) to investigate the structural basis of INH resistance conferred by these KatG variants. We present high\u2010resolution cryo\u2010EM structures that reveal heterogeneity in heme loading among the mutants. Detailed structural analysis highlights alterations in the hydrogen\u2010bonding network and substrate access channel unique to each variant, offering direct comparisons with the wild\u2010type (WT) KatG protein. Our findings provide a molecular explanation for clinical INH resistance and lay the groundwork for the rational design of next\u2010generation anti\u2010TB therapeutics.\n                  <\/jats:p>","DOI":"10.1002\/pro.70409","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T13:35:12Z","timestamp":1766496912000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Uncovering the structural impact of\n                    <scp>KatG<\/scp>\n                    Ser315 mutations in\n                    <i>Mycobacterium tuberculosis<\/i>\n                    via cryo\u2010\n                    <scp>EM<\/scp>"],"prefix":"10.1002","volume":"35","author":[{"given":"Thomas","family":"Allport","sequence":"first","affiliation":[{"name":"Department of Molecular and Cell Biology, University of Leicester Leicester Institute for Structural and Chemical Biology  Leicester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9606-8346","authenticated-orcid":false,"given":"Amanda K.","family":"Chaplin","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology, University of Leicester Leicester Institute for Structural and Chemical Biology  Leicester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,23]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1107\/S2059798318006551"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jgar.2018.02.009"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.5588\/ijtld.14.0864"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2666-5247(22)00359-7"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11033-022-07404-2"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.324"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.9.3373-3381.2004"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1002708"},{"key":"e_1_2_10_10_1","volume-title":"Peroxidases and Catalases: Biochemistry, Biophysics, Biotechnology and Physiology","author":"Dunford 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