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CydDC in nanodisc with heme-bound I
Structural highlights
FunctionCYDC_ECOLI Part of the ABC transporter complex CydDC that exports the reduced low-molecular-weight thiols cysteine and glutathione to the periplasm (PubMed:12393891, PubMed:16040611). Export of these thiol-containing redox-active molecules may be crucial for redox homeostasis in the periplasm, permitting correct assembly of various respiratory complexes and formation of correct disulfide bonds in periplasmic and secreted proteins (Probable). CydC contains transmembrane domains (TMD), which form a pore in the inner membrane, and an ATP-binding domain (NBD), which is responsible for energy generation (PubMed:24958725). Required for the assembly of functional cytochrome bd-type quinol oxidases and periplasmic c-type cytochromes (PubMed:15470119, PubMed:3032907, PubMed:7934832, PubMed:8181727). Overexpression of CydDC under anaerobic conditions also results in the formation of a heme biosynthesis-derived pigment, P-574 (PubMed:12375104). CydDC binds heme b, but heme is probably not transported by the complex and instead has a role in regulating ATPase activity (PubMed:24958725).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] Conversely, a more recent study suggests an alternative function of CydDC: authors suggest that CydDC does not mediate the export of L-cysteine but rather reduces cytoplasmic L-cystine to L-cysteine (PubMed:32900959). The principle function of CydDC would be to maintain the reduced state of cytoplasmic L-cysteine, thereby providing an important connection between sulfur metabolism, oxidative stress and resistance to antibiotics (PubMed:32900959).[12] Publication Abstract from PubMedHeme is an essential cofactor in numerous biological processes, including bacterial respiration. The ABC transporter CydDC facilitates the assembly and maturation of the cytochrome bd terminal oxidase by exporting heme and has been implicated in antibiotic resistance in bacteria. However, the dynamic conformations of CydDC in a native-like lipid bilayer remain unresolved, and its resistance mechanism is still elusive. Here, we determined high-resolution cryo-electron microscopy structures of nanodisc-reconstituted CydDC in the apo, nucleotide-bound and heme-bound states, providing direct structural evidence for its substrate-stimulated 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 cydC/D in antibiotic-resistant strains showed that elevated expression of cydC/D correlates with increased antibiotic resistance. Moreover, mutations at the heme-binding 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-mediated heme transport and potential drug efflux, and inform the development of antimicrobial strategies targeting the respiratory chain. Conformational Snapshots of CydDC in a Native Lipid Bilayer Coupling Heme Transport to Antibiotic Resistance.,Yang L, Zhang C, Lyu M, Luo Y, Zhang J, Chen Y, Luo L, Qiao W, Li X, Zhou Y, Wei Z, Xiao Y, Niu Q, Zhou J, He G, Ying B, Su Z, Chen H, Tang X, Dong H Adv Sci (Weinh). 2026 Jun 11:e76081. doi: 10.1002/advs.76081. PMID:42272423[13] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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