{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:19:38Z","timestamp":1768508378591,"version":"3.49.0"},"posted":{"date-parts":[[2024,1,31]]},"group-title":"Biochemistry","reference-count":52,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,3,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Transporters from the ABCC family have an essential role in detoxifying electrophilic compounds including metals, drugs, and lipids, often through conjugation with glutathione complexes. The Yeast Cadmium Factor 1 (Ycf1) transports glutathione alone as well as glutathione conjugated to toxic heavy metals including Cd\n                  <jats:sup>2+<\/jats:sup>\n                  , Hg\n                  <jats:sup>2+<\/jats:sup>\n                  , and As\n                  <jats:sup>3+<\/jats:sup>\n                  . To understand the complicated selectivity and promiscuity of heavy metal substrate binding, we determined the cryo-EM structure of Ycf1 bound to the substrate, oxidized glutathione. We systematically tested binding determinants with cellular survival assays against cadmium to determine how the substrate site accommodates differentsized metal complexes. We identify a \u201cflex-pocket\u201d for substrate binding that binds glutathione complexes asymmetrically and flexes to accommodate different size complexes.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>The molecular mechanism by which Ycf1 transports a broad array of substrates that are essential for cellular detoxification and redox homeostasis remains unknown in the field of cellular biology. Here, guided by the novel substrate bound structure of Ycf1, we discovered a bipartite binding mechanism that accommodates substrates of varying sizes while maintaining specificity. Four crucial ionic interactions govern substrate specificity by recognizing ligands with a glutathione moiety, complemented by a sizable pocket on the adjacent side for different glutathione complexes.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.01.31.578287","type":"posted-content","created":{"date-parts":[[2024,1,31]],"date-time":"2024-01-31T22:20:14Z","timestamp":1706739614000},"source":"Crossref","is-referenced-by-count":1,"title":["Structural Basis for Oxidized Glutathione Recognition by the Yeast Cadmium Factor 1"],"prefix":"10.64898","author":[{"given":"Tik Hang","family":"Soong","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clare","family":"Hotze","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nitesh Kumar","family":"Khandelwal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas 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