{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T18:50:14Z","timestamp":1783018214442,"version":"3.54.6"},"reference-count":65,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,14]],"date-time":"2023-02-14T00:00:00Z","timestamp":1676332800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"internal US FDA Chief Scientist Challenge grant"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Since November 2021, Omicron has been the dominant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant that causes the coronavirus disease 2019 (COVID-19) and has continuously impacted human health. Omicron sublineages are still increasing and cause increased transmission and infection rates. The additional 15 mutations on the receptor binding domain (RBD) of Omicron spike proteins change the protein conformation, enabling the Omicron variant to evade neutralizing antibodies. For this reason, many efforts have been made to design new antigenic variants to induce effective antibodies in SARS-CoV-2 vaccine development. However, understanding the different states of Omicron spike proteins with and without external molecules has not yet been addressed. In this review, we analyze the structures of the spike protein in the presence and absence of angiotensin-converting enzyme 2 (ACE2) and antibodies. Compared to previously determined structures for the wildtype spike protein and other variants such as alpha, beta, delta, and gamma, the Omicron spike protein adopts a partially open form. The open-form spike protein with one RBD up is dominant, followed by the open-form spike protein with two RBD up, and the closed-form spike protein with the RBD down. It is suggested that the competition between antibodies and ACE2 induces interactions between adjacent RBDs of the spike protein, which lead to a partially open form of the Omicron spike protein. The comprehensive structural information of Omicron spike proteins could be helpful for the efficient design of vaccines against the Omicron variant.<\/jats:p>","DOI":"10.3390\/ijms24043774","type":"journal-article","created":{"date-parts":[[2023,2,14]],"date-time":"2023-02-14T02:41:56Z","timestamp":1676342516000},"page":"3774","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Distinct Conformations of SARS-CoV-2 Omicron Spike Protein and Its Interaction with ACE2 and Antibody"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2078-6023","authenticated-orcid":false,"given":"Myeongsang","family":"Lee","sequence":"first","affiliation":[{"name":"National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marian","family":"Major","sequence":"additional","affiliation":[{"name":"Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8087-3968","authenticated-orcid":false,"given":"Huixiao","family":"Hong","sequence":"additional","affiliation":[{"name":"National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1002\/jmv.25749","article-title":"The transmission and diagnosis of 2019 novel coronavirus infection disease (COVID-19): A Chinese perspective","volume":"92","author":"Han","year":"2020","journal-title":"J. Med. Virol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/S0140-6736(20)30251-8","article-title":"Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding","volume":"395","author":"Lu","year":"2020","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/s41586-020-2008-3","article-title":"A new coronavirus associated with human respiratory disease in China","volume":"579","author":"Wu","year":"2020","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"628370","DOI":"10.3389\/fmed.2021.628370","article-title":"A Review of SARS-CoV2: Compared With SARS-CoV and MERS-CoV","volume":"8","author":"Zhou","year":"2021","journal-title":"Front. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1038\/s41401-020-0485-4","article-title":"Structural and functional properties of SARS-CoV-2 spike protein: Potential antivirus drug development for COVID-19","volume":"41","author":"Huang","year":"2020","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"eabf3671","DOI":"10.1126\/sciadv.abf3671","article-title":"The SARS-CoV-2 Spike variant D614G favors an open conformational state","volume":"7","author":"Mansbach","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.cell.2020.02.058","article-title":"Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein","volume":"181","author":"Walls","year":"2020","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/nature12005","article-title":"Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC","volume":"495","author":"Raj","year":"2013","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1016\/j.cell.2020.03.045","article-title":"Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2","volume":"181","author":"Wang","year":"2020","journal-title":"Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1126\/science.abb2507","article-title":"Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation","volume":"367","author":"Wrapp","year":"2020","journal-title":"Science"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1016\/j.bpj.2021.02.007","article-title":"Biomechanical characterization of SARS-CoV-2 spike RBD and human ACE2 protein-protein interaction","volume":"120","author":"Cao","year":"2021","journal-title":"Biophys. J."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Nugent, M.A. (2022). The Future of the COVID-19 Pandemic: How Good (or Bad) Can the SARS-CoV2 Spike Protein Get?. Cells, 11.","DOI":"10.3390\/cells11050855"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1126\/science.abd3255","article-title":"Free fatty acid binding pocket in the locked structure of SARS-CoV-2 spike protein","volume":"370","author":"Toelzer","year":"2020","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1038\/s41594-020-0478-5","article-title":"A thermostable, closed SARS-CoV-2 spike protein trimer","volume":"27","author":"Xiong","year":"2020","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1038\/s41422-020-00430-4","article-title":"The SARS-CoV-2 spike protein: Balancing stability and infectivity","volume":"30","author":"Berger","year":"2020","journal-title":"Cell Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1126\/science.abn8863","article-title":"Structures of the Omicron spike trimer with ACE2 and an anti-Omicron antibody","volume":"375","author":"Yin","year":"2022","journal-title":"Science"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1126\/science.abd4251","article-title":"Distinct conformational states of SARS-CoV-2 spike protein","volume":"369","author":"Cai","year":"2020","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1016\/j.str.2021.04.006","article-title":"Conformational flexibility and structural variability of SARS-CoV2 S protein","volume":"29","author":"Pramanick","year":"2021","journal-title":"Structure"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"075101","DOI":"10.1063\/5.0011141","article-title":"Conformational transition of SARS-CoV-2 spike glycoprotein between its closed and open states","volume":"153","author":"Gur","year":"2020","journal-title":"J. Chem. Phys."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"13184","DOI":"10.1080\/07391102.2021.1982775","article-title":"Mutational profile confers increased stability of SARS-CoV-2 spike protein in Brazilian isolates","volume":"40","author":"Santos","year":"2021","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e2100943118","DOI":"10.1073\/pnas.2100943118","article-title":"Distant residues modulate conformational opening in SARS-CoV-2 spike protein","volume":"118","author":"Ray","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Rotondo, J.C., Martini, F., Maritati, M., Caselli, E., Gallenga, C.E., Guarino, M., De Giorgio, R., Mazziotta, C., Tramarin, M.L., and Badiale, G. (2022). Advanced Molecular and Immunological Diagnostic Methods to Detect SARS-CoV-2 Infection. Microorganisms, 10.","DOI":"10.3390\/microorganisms10061193"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4780","DOI":"10.1002\/jmv.27927","article-title":"Omicron (BA.1) and sub-variants (BA.1.1, BA.2, and BA.3) of SARS-CoV-2 spike infectivity and pathogenicity: A comparative sequence and structural-based computational assessment","volume":"94","author":"Kumar","year":"2022","journal-title":"J. Med. Virol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.1002\/jmv.27526","article-title":"Omicron and Delta variant of SARS-CoV-2: A comparative computational study of spike protein","volume":"94","author":"Kumar","year":"2022","journal-title":"J. Med. Virol."},{"key":"ref_25","unstructured":"(2015). Schr\u00f6dinger LLC."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3602","DOI":"10.1038\/s41467-022-30681-1","article-title":"Neutralization of Omicron BA.1, BA.2, and BA.3 SARS-CoV-2 by 3 doses of BNT162b2 vaccine","volume":"13","author":"Kurhade","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4617","DOI":"10.1038\/s41467-022-32298-w","article-title":"Antibody affinity and cross-variant neutralization of SARS-CoV-2 Omicron BA.1, BA.2 and BA.3 following third mRNA vaccination","volume":"13","author":"Bellusci","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1038\/s41467-022-28544-w","article-title":"Neutralization against Omicron SARS-CoV-2 from previous non-Omicron infection","volume":"13","author":"Zou","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1016\/j.chom.2022.05.001","article-title":"Antibody evasion of SARS-CoV-2 Omicron BA.1, BA.1.1, BA.2, and BA.3 sub-lineages","volume":"30","author":"Ai","year":"2022","journal-title":"Cell Host Microbe"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1038\/s41586-022-04980-y","article-title":"BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron infection","volume":"608","author":"Cao","year":"2022","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2050","DOI":"10.1016\/j.molcel.2022.03.028","article-title":"Structural diversity of the SARS-CoV-2 Omicron spike","volume":"82","author":"Gobeil","year":"2022","journal-title":"Mol. Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"111009","DOI":"10.1016\/j.celrep.2022.111009","article-title":"Cryo-EM structures of SARS-CoV-2 Omicron BA.2 spike","volume":"39","author":"Stalls","year":"2022","journal-title":"Cell Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1016\/j.cell.2022.01.019","article-title":"Structural and functional characterizations of infectivity and immune evasion of SARS-CoV-2 Omicron","volume":"185","author":"Cui","year":"2022","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1038\/s41586-022-04581-9","article-title":"Molecular basis of receptor binding and antibody neutralization of Omicron","volume":"604","author":"Hong","year":"2022","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"eabh1766","DOI":"10.1126\/science.abh1766","article-title":"Ultrapotent antibodies against diverse and highly transmissible SARS-CoV-2 variants","volume":"373","author":"Wang","year":"2021","journal-title":"Science"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e00480-22","DOI":"10.1128\/jvi.00480-22","article-title":"Structural Study of SARS-CoV-2 Antibodies Identifies a Broad-Spectrum Antibody That Neutralizes the Omicron Variant by Disassembling the Spike Trimer","volume":"96","author":"Zhan","year":"2022","journal-title":"J. Virol."},{"key":"ref_38","unstructured":"Ni, D., Lau, K., Turelli, P., Raclot, C., Beckert, B., Nazarov, S., Pojer, F., Myasnikov, A., Stahlberg, H., and Trono, D. (2021). Structural analysis of the Spike of the Omicron SARS-COV-2 variant by cryo-EM and implications for immune evasion. bioRxiv."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"110729","DOI":"10.1016\/j.celrep.2022.110729","article-title":"Structural and functional impact by SARS-CoV-2 Omicron spike mutations","volume":"39","author":"Zhang","year":"2022","journal-title":"Cell Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1126\/science.abn7760","article-title":"SARS-CoV-2 Omicron variant: Antibody evasion and cryo-EM structure of spike protein\u2014ACE2 complex","volume":"375","author":"Mannar","year":"2022","journal-title":"Science"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1038\/s41467-022-28882-9","article-title":"Cryo-EM structure of a SARS-CoV-2 omicron spike protein ectodomain","volume":"13","author":"Ye","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Hong, Q., Han, W., Li, J., Xu, S., Wang, Y., Li, Z., Wang, Y., Zhang, C., Huang, Z., and Cong, Y. (2022). Molecular basis of SARS-CoV-2 Omicron variant receptor engagement and antibody evasion and neutralization. bioRxiv.","DOI":"10.1101\/2022.01.10.475532"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1038\/s41422-022-00672-4","article-title":"Structural and biochemical mechanism for increased infectivity and immune evasion of Omicron BA.2 variant compared to BA.1 and their possible mouse origins","volume":"32","author":"Xu","year":"2022","journal-title":"Cell Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4958","DOI":"10.1038\/s41467-022-32665-7","article-title":"Omicron SARS-CoV-2 mutations stabilize spike up-RBD conformation and lead to a non-RBM-binding monoclonal antibody escape","volume":"13","author":"Zhao","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1016\/j.chom.2022.09.018","article-title":"Characterization of the enhanced infectivity and antibody evasion of Omicron BA.2.75","volume":"30","author":"Cao","year":"2022","journal-title":"Cell Host Microbe"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1126\/science.abn8652","article-title":"Structural basis of SARS-CoV-2 Omicron immune evasion and receptor engagement","volume":"375","author":"McCallum","year":"2022","journal-title":"Science"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1038\/s41586-021-04386-2","article-title":"Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift","volume":"602","author":"Cameroni","year":"2022","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Barre, A., Klonjkowski, B., Benoist, H., and Roug\u00e9, P. (2022). How Do Point Mutations Enhancing the Basic Character of the RBDs of SARS-CoV-2 Variants Affect Their Transmissibility and Infectivity Capacities?. Viruses, 14.","DOI":"10.3390\/v14040783"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1056\/NEJMc2201849","article-title":"Neutralization of the SARS-CoV-2 Omicron BA.1 and BA.2 Variants","volume":"386","author":"Yu","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1038\/s41591-022-01792-5","article-title":"Serum neutralization of SARS-CoV-2 Omicron sublineages BA.1 and BA.2 in patients receiving monoclonal antibodies","volume":"28","author":"Bruel","year":"2022","journal-title":"Nat. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3375","DOI":"10.1038\/s41467-022-31115-8","article-title":"Anatomy of Omicron BA.1 and BA.2 neutralizing antibodies in COVID-19 mRNA vaccinees","volume":"13","author":"Andreano","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"eadd2032","DOI":"10.1126\/sciadv.add2032","article-title":"Structural insights for neutralization of Omicron variants BA.1, BA.2, BA.4, and BA.5 by a broadly neutralizing SARS-CoV-2 antibody","volume":"8","author":"Kumar","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"110770","DOI":"10.1016\/j.celrep.2022.110770","article-title":"Structures of Omicron spike complexes and implications for neutralizing antibody development","volume":"39","author":"Guo","year":"2022","journal-title":"Cell Rep."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Lippi, G., Henry, B.M., and Plebani, M. (2021). Anti-SARS-CoV-2 Antibodies Testing in Recipients of COVID-19 Vaccination: Why, When, and How?. Diagnostics, 11.","DOI":"10.3390\/diagnostics11060941"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1930636","DOI":"10.1080\/19420862.2021.1930636","article-title":"A human antibody of potent efficacy against SARS-CoV-2 in rhesus macaques showed strong blocking activity to B.1.351","volume":"13","author":"Gu","year":"2021","journal-title":"mAbs"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1016\/j.chom.2022.03.035","article-title":"35B5 antibody potently neutralizes SARS-CoV-2 Omicron by disrupting the N-glycan switch via a conserved spike epitope","volume":"30","author":"Wang","year":"2022","journal-title":"Cell Host Microbe"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1038\/s41422-022-00684-0","article-title":"A broadly neutralizing antibody against SARS-CoV-2 Omicron variant infection exhibiting a novel trimer dimer conformation in spike protein binding","volume":"32","author":"Wang","year":"2022","journal-title":"Cell Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"eabp9312","DOI":"10.1126\/sciimmunol.abp9312","article-title":"An ACE2-blocking antibody confers broad neutralization and protection against Omicron and other SARS-CoV-2 variants of concern","volume":"7","author":"Du","year":"2022","journal-title":"Sci. Immunol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1016\/j.cell.2022.03.009","article-title":"Broad neutralization of SARS-CoV-2 variants by an inhalable bispecific single-domain antibody","volume":"185","author":"Li","year":"2022","journal-title":"Cell"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"eabn8897","DOI":"10.1126\/science.abn8897","article-title":"Structural basis for potent antibody neutralization of SARS-CoV-2 variants including B.1.1.529","volume":"376","author":"Zhou","year":"2022","journal-title":"Science"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"104431","DOI":"10.1016\/j.isci.2022.104431","article-title":"Structural and functional analysis of an inter-Spike bivalent neutralizing antibody against SARS-CoV-2 variants","volume":"25","author":"Li","year":"2022","journal-title":"iScience"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Ren, P., Hu, Y., Peng, L., Yang, L., Suzuki, K., Fang, Z., Bai, M., Zhou, L., Feng, Y., and Xiong, Y. (2022). Function and Cryo-EM structures of broadly potent bispecific antibodies against multiple SARS-CoV-2 Omicron sublineages. bioRxiv.","DOI":"10.1101\/2022.08.09.503414"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1038\/s41586-022-04466-x","article-title":"Memory B cell repertoire from triple vaccinees against diverse SARS-CoV-2 variants","volume":"603","author":"Wang","year":"2022","journal-title":"Nature"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1038\/s41564-022-01198-6","article-title":"Patient-derived monoclonal antibody neutralizes SARS-CoV-2 Omicron variants and confers full protection in monkeys","volume":"7","author":"Fenwick","year":"2022","journal-title":"Nat. Microbiol."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Wang, K., Cao, Y., Zhou, Y., Wu, J., Jia, Z., Hu, Y., Yisimayi, A., Fu, W., Wang, L., and Liu, P. (2021). A third dose of inactivated vaccine augments the potency, breadth, and duration of anamnestic responses against SARS-CoV-2. medRxiv.","DOI":"10.1101\/2021.09.02.21261735"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/3774\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:34:19Z","timestamp":1760121259000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/3774"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,14]]},"references-count":65,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ijms24043774"],"URL":"https:\/\/doi.org\/10.3390\/ijms24043774","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,14]]}}}