dc.contributor.author | Lenza, Maria Pia | |
dc.contributor.author | Atxabal Arrasate, Unai | |
dc.contributor.author | Nycholat, Corwin | |
dc.contributor.author | Oyenarte Santamaría, Iker | |
dc.contributor.author | Franconetti García, Antonio | |
dc.contributor.author | Quintana García, Jon Imanol | |
dc.contributor.author | Delgado, Sandra | |
dc.contributor.author | Núñez Franco, Reyes | |
dc.contributor.author | Garnica Marroquín, Carmen Teresa | |
dc.contributor.author | Coelho, Helena | |
dc.contributor.author | Unione, Luca | |
dc.contributor.author | Jiménez Oses, Gonzalo | |
dc.contributor.author | Marcelo, Filipa | |
dc.contributor.author | Schubert, Mario | |
dc.contributor.author | Paulson, James C. | |
dc.contributor.author | Jiménez Barbero, Jesús | |
dc.contributor.author | Ereño Orbea, June | |
dc.date.accessioned | 2023-03-20T16:09:39Z | |
dc.date.available | 2023-03-20T16:09:39Z | |
dc.date.issued | 2023-01 | |
dc.identifier.citation | JACS Au 3(1) : 204-215 (2023) | es_ES |
dc.identifier.issn | 2691-3704 | |
dc.identifier.uri | http://hdl.handle.net/10810/60416 | |
dc.description.abstract | Human sialic acid binding immunoglobulin-like lectin-8 (Siglec-8) is an inhibitory receptor that triggers eosinophil apoptosis and can inhibit mast cell degranulation when engaged by specific monoclonal antibodies (mAbs) or sialylated ligands. Thus, Siglec-8 has emerged as a critical negative regulator of inflammatory responses in diverse diseases, such as allergic airway inflammation. Herein, we have deciphered the molecular recognition features of the interaction of Siglec-8 with the mAb lirentelimab (2C4, under clinical development) and with a sialoside mimetic with the potential to suppress mast cell degranulation. The three-dimensional structure of Siglec-8 and the fragment antigen binding (Fab) portion of the anti-Siglec-8 mAb 2C4, solved by X-ray crystallography, reveal that 2C4 binds close to the carbohydrate recognition domain (V-type Ig domain) on Siglec-8. We have also deduced the binding mode of a high-affinity analogue of its sialic acid ligand (9-N-napthylsufonimide-Neu5Ac, NSANeuAc) using a combination of NMR spectroscopy and X-ray crystallography. Our results show that the sialoside ring of NSANeuAc binds to the canonical sialyl binding pocket of the Siglec receptor family and that the high affinity arises from the accommodation of the NSA aromatic group in a nearby hydrophobic patch formed by the N-terminal tail and the unique G–G′ loop. The results reveal the basis for the observed high affinity of this ligand and provide clues for the rational design of the next generation of Siglec-8 inhibitors. Additionally, the specific interactions between Siglec-8 and the N-linked glycans present on the high-affinity receptor FcεRIα have also been explored by NMR. | es_ES |
dc.description.sponsorship | This work was supported by operating grant PID2019-107770RA-I00 (J.E.-O.) from the Agencia Estatal Investigación of Spain and by the European Research Council (ERC-2017-AdG, 788143-RECGLYCANMR to J.J.-B.). We also thank the Marie-Skłodowska-Curie actions (ITN Glytunes grant agreement no. 956758 to J.E.-O and ITN BactiVax under grant agreement no. 860325 to U.A.). Additional funding was provided by CIBER, an initiative of Instituto de Salud Carlos III (ISCIII), Madrid, Spain. We also thank the Ikerbasque Basque Foundation of Science and the Spanish Ministry of Economy, Industry and Competitiveness (for the postdoctoral contract Juan de la Cierva Incorporación to J.E-O). X-ray diffraction experiments described in this paper were performed using the XALOC synchrotron beamline at ALBA (Spain) and PXIII in Swiss Light Source (Switzerland). | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | American Chemical Society | es_ES |
dc.relation | info:eu-repo/grantAgreement/EC/H2020/956758 | es_ES |
dc.relation | info:eu-repo/grantAgreement/EC/H2020/860325 | es_ES |
dc.relation | info:eu-repo/grantAgreement/MICINN/PID2019-107770RA-I00 | es_ES |
dc.relation | info:eu-repo/grantAgreement/EC/ERC/788143 | es_ES |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/es/ | * |
dc.subject | siglec | es_ES |
dc.subject | sialic acid | es_ES |
dc.subject | antibody | es_ES |
dc.subject | X-ray crystallography | es_ES |
dc.subject | N M R | es_ES |
dc.title | Structures of the Inhibitory Receptor Siglec-8 in Complex with a High-Affinity Sialoside Analogue and a Therapeutic Antibody | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.rights.holder | © 2022 The Authors. Published by American Chemical Society. Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) | es_ES |
dc.rights.holder | Atribución-NoComercial-SinDerivadas 3.0 España | * |
dc.relation.publisherversion | https://pubs.acs.org/doi/10.1021/jacsau.2c00592 | es_ES |
dc.identifier.doi | 10.1021/jacsau.2c00592 | |
dc.contributor.funder | European Commission | |
dc.departamentoes | Química Orgánica e Inorgánica | es_ES |
dc.departamentoeu | Kimika Organikoa eta Ez-Organikoa | es_ES |