7QU6

Crystal structure of the N-terminal domain of Siglec-8

7QU6 の概要

• エントリーDOI: 10.2210/pdb7qu6/pdb
• 分子名称: Sialic acid-binding Ig-like lectin 8 (2 entities in total)
• 機能のキーワード: siglec, sialic acid, antibody, immune system
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 105830.85

構造登録者

Lenza, M.P.,Atxabal, U.,Nycholat, C.M.,Oyenarte, I.,Paulson, J.C.,Franconetti, A.,Quintana, J.I.,Unione, L.,Delgado, S.,Jimenez-Barbero, J.,Ereno-Orbea, J. (登録日: 2022-01-17, 公開日: 2023-01-18, 最終更新日: 2024-11-13)

主引用文献

Lenza, M.P.,Atxabal, U.,Nycholat, C.,Oyenarte, I.,Franconetti, A.,Quintana, J.I.,Delgado, S.,Nunez-Franco, R.,Garnica Marroquin, C.T.,Coelho, H.,Unione, L.,Jimenez-Oses, G.,Marcelo, F.,Schubert, M.,Paulson, J.C.,Jimenez-Barbero, J.,Ereno-Orbea, J.
Structures of the Inhibitory Receptor Siglec-8 in Complex with a High-Affinity Sialoside Analogue and a Therapeutic Antibody.
Jacs Au, 3:204-215, 2023

PubMed 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--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 -' 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.

PubMed: 36711084
DOI: 10.1021/jacsau.2c00592

実験手法

X-RAY DIFFRACTION (2.34 Å)