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The ABC transporter CydDC facilitates the assembly and maturation of the cytochrome\n                    <jats:italic>bd<\/jats:italic>\n                    terminal oxidase by exporting heme and has been implicated in antibiotic resistance in bacteria. However, the dynamic conformations of CydDC in a native\u2010like lipid bilayer remain unresolved, and its resistance mechanism is still elusive. Here, we determined high\u2010resolution cryo\u2010electron microscopy structures of nanodisc\u2010reconstituted CydDC in the apo, nucleotide\u2010bound and heme\u2010bound states, providing direct structural evidence for its substrate\u2010stimulated hydrolysis mechanism. In vivo and in vitro biochemical characterization identified key residues of CydDC that are critical for substrate binding and transport. Bioinformatics analysis further demonstrated that CydDC is highly conserved across bacterial species. Transcriptomic profiling of\n                    <jats:italic>cydC\/D<\/jats:italic>\n                    in antibiotic\u2010resistant strains showed that elevated expression of\n                    <jats:italic>cydC\/D<\/jats:italic>\n                    correlates with increased antibiotic resistance. Moreover, mutations at the heme\u2010binding sites altered bacterial susceptibility to multiple antibiotics, suggesting that the exporting activity of CydDC may also contribute directly to drug resistance. Together, these findings provide mechanistic insights into CydDC\u2010mediated heme transport and potential drug efflux, and inform the development of antimicrobial strategies targeting the respiratory chain.\n                  <\/jats:p>","DOI":"10.1002\/advs.76081","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T08:01:01Z","timestamp":1781164861000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Conformational Snapshots of CydDC in a Native Lipid Bilayer Coupling Heme Transport to Antibiotic Resistance"],"prefix":"10.1002","volume":"13","author":[{"given":"Lili","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine State Key Laboratory of Biotherapy and Cancer Center National Clinical Research Center for Geriatrics West China Hospital Sichuan University  Chengdu 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