biostudies-literatureLenza MPCenter for International Business Education and Research, University of Illinois at Urbana-ChampaignH2020 Marie Sklodowska-Curie ActionsEuropean Research CouncilAgencia Estatal de Investigaci?n204-215https://www.ebi.ac.uk/biostudies/studies/S-EPMC9875244biostudies-literatureUnknown3(1)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 binJACS AuStructures of the Inhibitory Receptor Siglec-8 in Complex with a High-Affinity Sialoside Analogue and a Therapeutic Antibody.PMC9875244788143PID2019-107770RA-I00788143-RECGLYCANMR956758860325Lenza MPQuintana JIAtxabal UDelgado SEreno-Orbea JNunez-Franco RUnione LFranconetti AMarcelo FSchubert MOyenarte IPaulson JCGarnica Marroquin CTJimenez-Oses GNycholat CCoelho HJimenez-Barbero JfalseStructures of the Inhibitory Receptor Siglec-8 in Complex with a High-Affinity Sialoside Analogue and a Therapeutic Antibody.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 bin2023-01-01T00:00:00Z2023 Jan2026-07-14T19:05:32.202Z2025-04-07T03:18:57.07ZS-EPMC98752443671108410.1021/jacsau.2c00592