{"doi":"10.1126/sciadv.abl5508","title":"Structure of the Wilson disease copper transporter ATP7B","abstract":"<jats:p>ATP7A and ATP7B, two homologous copper-transporting P1B-type ATPases, play crucial roles in cellular copper homeostasis, and mutations cause Menkes and Wilson diseases, respectively. ATP7A/B contains a P-type ATPase core consisting of a membrane transport domain and three cytoplasmic domains, the A, P, and N domains, and a unique amino terminus comprising six consecutive metal-binding domains. Here, we present a cryo–electron microscopy structure of frog ATP7B in a copper-free state. Interacting with both the A and P domains, the metal-binding domains are poised to exert copper-dependent regulation of ATP hydrolysis coupled to transmembrane copper transport. A ring of negatively charged residues lines the cytoplasmic copper entrance that is presumably gated by a conserved basic residue sitting at the center. Within the membrane, a network of copper-coordinating ligands delineates a stepwise copper transport pathway. This work provides the first glimpse into the structure and function of ATP7 proteins and facilitates understanding of disease mechanisms and development of rational therapies.</jats:p>","journal":"Science Advances","year":2022,"id":655242,"datarank":0.6937459219926407,"base_score":4.624972813284271,"endowment":4.624972813284271,"self_citation_contribution":0.6937459219926407,"citation_network_contribution":0.0,"self_endowment_contribution":0.6937459219926407,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":101,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":831411,"name":"SeCheol Oh","orcid":"0000-0002-1685-5922","position":1,"is_corresponding":false},{"id":506033,"name":"Zengqin Deng","orcid":"0000-0002-5658-2068","position":2,"is_corresponding":false},{"id":873148,"name":"Suhaila Rahman","orcid":"0000-0002-7946-5155","position":3,"is_corresponding":false},{"id":292045,"name":"Richard K. Hite","orcid":"0000-0003-0496-0669","position":4,"is_corresponding":false},{"id":506037,"name":"Peng Yuan","orcid":"0000-0002-5660-225X","position":5,"is_corresponding":false},{"id":1265599,"name":"Ryan M. Bitter","orcid":"0000-0001-9272-3609","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Structure of the Wilson disease copper transporter ATP7B.","abstract":"ATP7A and ATP7B, two homologous copper-transporting P1B-type ATPases, play crucial roles in cellular copper homeostasis, and mutations cause Menkes and Wilson diseases, respectively. ATP7A/B contains a P-type ATPase core consisting of a membrane transport domain and three cytoplasmic domains, the A, P, and N domains, and a unique amino terminus comprising six consecutive metal-binding domains. Here, we present a cryo-electron microscopy structure of frog ATP7B in a copper-free state. Interacting with both the A and P domains, the metal-binding domains are poised to exert copper-dependent regulation of ATP hydrolysis coupled to transmembrane copper transport. A ring of negatively charged residues lines the cytoplasmic copper entrance that is presumably gated by a conserved basic residue sitting at the center. Within the membrane, a network of copper-coordinating ligands delineates a stepwise copper transport pathway. This work provides the first glimpse into the structure and function of ATP7 proteins and facilitates understanding of disease mechanisms and development of rational therapies.","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"35245129","pmcid":"PMC8896786","openalex_id":null,"authors":[],"funders":[{"funder_name":"NCI NIH HHS","grant_id":"P30 CA008748","title":null},{"funder_name":"NINDS NIH HHS","grant_id":"R01 NS109307","title":null},{"funder_name":"National Institutes of Health","grant_id":"2P30CA008748-43","title":"MOUSE GENETICS"},{"funder_name":"National Institutes of Health","grant_id":"5R01NS109307-04","title":"Molecular Mechanisms of Copper Transport"}],"total_grants":4,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"gold","license":"cc-by-nc","oa_locations":[{"url":"https://doi.org/10.1126/sciadv.abl5508","host_type":"publisher"},{"url":"https://digitalcommons.wustl.edu/open_access_pubs/11936","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/8896786","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC8896786","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC8896786?pdf=render","host_type":"Europe_PMC"},{"url":"https://www.science.org/doi/pdf/10.1126/sciadv.abl5508?download=true","host_type":""},{"url":"https://pubmed.ncbi.nlm.nih.gov/35245129","host_type":""},{"url":"http://dx.doi.org/10.1126/sciadv.abl5508","host_type":""},{"url":"https://doi.org/https://doi.org/10.1126/sciadv.abl5508","host_type":""}],"fields_of_study":["0301 basic medicine","0303 health sciences","03 medical and health sciences"],"mesh_terms":[],"keywords":["500","Biomedicine and Life Sciences"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"pdb"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-11T10:11:02.519630Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}