6TCS

Crystal structure of the omalizumab scFv

6TCS の概要

• エントリーDOI: 10.2210/pdb6tcs/pdb
• 分子名称: Omalizumab scFv, DI(HYDROXYETHYL)ETHER (3 entities in total)
• 機能のキーワード: fab, antibody, immunoglobulin, immune system
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29702.33

構造登録者

Mitropoulou, A.N.,Ceska, T.,Beavil, A.J.,Henry, A.J.,McDonnell, J.M.,Sutton, B.J.,Davies, A.M. (登録日: 2019-11-06, 公開日: 2020-03-18, 最終更新日: 2024-10-09)

主引用文献

Mitropoulou, A.N.,Ceska, T.,Heads, J.T.,Beavil, A.J.,Henry, A.J.,McDonnell, J.M.,Sutton, B.J.,Davies, A.M.
Engineering the Fab fragment of the anti-IgE omalizumab to prevent Fab crystallization and permit IgE-Fc complex crystallization.
Acta Crystallogr.,Sect.F, 76:116-129, 2020

PubMed Abstract: Immunoglobulin E (IgE) plays a central role in the allergic response, in which cross-linking of allergen by FcεRI-bound IgE triggers mast cell and basophil degranulation and the release of inflammatory mediators. The high-affinity interaction between IgE and FcεRI is a long-standing target for therapeutic intervention in allergic disease. Omalizumab is a clinically approved anti-IgE monoclonal antibody that binds to free IgE, also with high affinity, preventing its interaction with FcεRI. All attempts to crystallize the pre-formed complex between the omalizumab Fab and the Fc region of IgE (IgE-Fc), to understand the structural basis for its mechanism of action, surprisingly failed. Instead, the Fab alone selectively crystallized in different crystal forms, but their structures revealed intermolecular Fab/Fab interactions that were clearly strong enough to disrupt the Fab/IgE-Fc complexes. Some of these interactions were common to other Fab crystal structures. Mutations were therefore designed to disrupt two recurring packing interactions observed in the omalizumab Fab crystal structures without interfering with the ability of the omalizumab Fab to recognize IgE-Fc; this led to the successful crystallization and subsequent structure determination of the Fab/IgE-Fc complex. The mutagenesis strategy adopted to achieve this result is applicable to other intractable Fab/antigen complexes or systems in which Fabs are used as crystallization chaperones.

PubMed: 32133997
DOI: 10.1107/S2053230X20001466

実験手法

X-RAY DIFFRACTION (2.3 Å)