dc.contributor.author | Rujas Díez, Edurne | |
dc.contributor.author | Cui, Hong | |
dc.contributor.author | Sicard, Taylor | |
dc.contributor.author | Semesi, Anthony | |
dc.contributor.author | Julien, Jean-Philippe | |
dc.date.accessioned | 2021-02-11T09:40:15Z | |
dc.date.available | 2021-02-11T09:40:15Z | |
dc.date.issued | 2020-10-08 | |
dc.identifier.citation | Nature Communications 11(1) : (2020) // Article ID 5066 | es_ES |
dc.identifier.issn | 2041-1723 | |
dc.identifier.uri | http://hdl.handle.net/10810/50139 | |
dc.description.abstract | The inducible co-stimulator (ICOS) is a member of the CD28/B7 superfamily, and delivers a positive co-stimulatory signal to activated T cells upon binding to its ligand (ICOS-L). Dysregulation of this pathway has been implicated in autoimmune diseases and cancer, and is currently under clinical investigation as an immune checkpoint blockade. Here, we describe the molecular interactions of the ICOS/ICOS-L immune complex at 3.3 Ao resolution. A central FDPPPF motif and residues within the CC' loop of ICOS are responsible for the specificity of the interaction with ICOS-L, with a distinct receptor binding orientation in comparison to other family members. Furthermore, our structure and binding data reveal that the ICOS N110 N-linked glycan participates in ICOS-L binding. In addition, we report crystal structures of ICOS and ICOS-L in complex with monoclonal antibodies under clinical evaluation in immunotherapy. Strikingly, antibody paratopes closely mimic receptor-ligand binding core interactions, in addition to contacting peripheral residues to confer high binding affinities. Our results uncover key molecular interactions of an immune complex central to human adaptive immunity and have direct implications for the ongoing development of therapeutic interventions targeting immune checkpoint receptors. The inducible co-stimulator (ICOS) is a member of the CD28/B7 superfamily, binding its ligand (ICOS-L) on activated T cells. The structure of the ICOS/ICOS-L complex reveals a distinct receptor binding orientation. The structures of ICOS and ICOS-L in complex with potentially therapeutic antibodies suggest the structural basis of such antibodies' efficacies and high binding affinities. | es_ES |
dc.description.sponsorship | This work was supported by the European Union's Horizon 2020 research and innovation program under Marie Sklodowska-Curie grant 790012 (E.R.), by operating grant PJT-148811 from the Canadian Institutes of Health Research (J.P.J.), the CIFAR Azrieli Global Scholar program (J.P.J.), the Ontario Early Researcher Awards program (J.P.J.), and the Canada Research Chairs program (J.P.J.). T.S. is a recipient of a Vanier Canada Graduate Scholarship. The BLI instrument was accessed at the Structural & Biophysical Core Facility, The Hospital for Sick Children, supported by the Canada Foundation for Innovation and Ontario Research Fund. X-ray diffraction experiments were performed at GM/CA@APS, which has been funded in whole or in part with federal funds from the National Cancer Institute (ACB-12002) and the National Institute of General Medical Sciences (AGM -12006). The Eiger 16M detector at GM/CA-XSD was funded by NIH grant S10 OD012289. This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science user facility operated for the DOE Office of Science by Argonne National Laboratory under contract DE-ACO2-06CH11357. X-ray diffraction experiments were also performed at the NSLS-II, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by BNL under Contract No. DE -5C0012704. The Life Science Biomedical Technology Research resource is primarily supported by the National Institute of Health, National Institute of General Medical Sciences (NIGMS) through a Biomedical Technology Research Resource P41 grant (P41GM111244), and by the DOE Office of Biological and Environmental Research (KP1605010). | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Nature | es_ES |
dc.relation | info:eu-repo/grantAgreement/EC/H2020/790012 | es_ES |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/es/ | * |
dc.subject | inducible costimulatory molecule | es_ES |
dc.subject | receptor-binding site | es_ES |
dc.subject | crystal-structure | es_ES |
dc.subject | co-stimulation | es_ES |
dc.subject | cell differentiation | es_ES |
dc.subject | T-cells | es_ES |
dc.subject | ICOS | es_ES |
dc.subject | ligand | es_ES |
dc.subject | activation | es_ES |
dc.subject | expression | es_ES |
dc.title | Structural Characterization of the ICOS/ICOS-L Immune Complex Reveals High Molecular Mimicry by Therapeutic Antibodies | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.rights.holder | This article is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0) | es_ES |
dc.rights.holder | Atribución 3.0 España | * |
dc.relation.publisherversion | https://www.nature.com/articles/s41467-020-18828-4 | es_ES |
dc.identifier.doi | 10.1038/s41467-020-18828-4 | |
dc.contributor.funder | European Commission | |
dc.departamentoes | Bioquímica y biología molecular | es_ES |
dc.departamentoeu | Biokimika eta biologia molekularra | es_ES |