6UGA

ch28/11 Fab (monoclinic form)

6UGA の概要

• エントリーDOI: 10.2210/pdb6uga/pdb
• 分子名称: ch28/11 Fab light chain, ch28/11 Fab heavy chain, methanesulfonic acid, ... (4 entities in total)
• 機能のキーワード: immunoglobulin, chimeric antibody, antigen binding fragment, immune system
• 由来する生物種: Mus musculus (Mouse); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 92463.29

構造登録者

Soliman, C.,Ramsland, P.A. (登録日: 2019-09-26, 公開日: 2019-12-18, 最終更新日: 2024-11-06)

主引用文献

Soliman, C.,Chua, J.X.,Vankemmelbeke, M.,McIntosh, R.S.,Guy, A.J.,Spendlove, I.,Durrant, L.G.,Ramsland, P.A.
The terminal sialic acid of stage-specific embryonic antigen-4 has a crucial role in binding to a cancer-targeting antibody.
J.Biol.Chem., 295:1009-1020, 2020

PubMed Abstract: Cancer remains a leading cause of morbidity and mortality worldwide, requiring ongoing development of targeted therapeutics such as monoclonal antibodies. Carbohydrates on embryonic cells are often highly expressed in cancer and are therefore attractive targets for antibodies. Stage-specific embryonic antigen-4 (SSEA-4) is one such glycolipid target expressed in many cancers, including breast and ovarian carcinomas. Here, we defined the structural basis for recognition of SSEA-4 by a novel monospecific chimeric antibody (ch28/11). Five X-ray structures of ch28/11 Fab complexes with the SSEA-4 glycan headgroup, determined at 1.5-2.7 Å resolutions, displayed highly similar three-dimensional structures indicating a stable binding mode. The structures also revealed that by adopting a horseshoe-shaped conformation in a deep groove, the glycan headgroup likely sits flat against the membrane to allow the antibody to interact with SSEA-4 on cancer cells. Moreover, we found that the terminal sialic acid of SSEA-4 plays a dominant role in dictating the exquisite specificity of the ch28/11 antibody. This observation was further supported by molecular dynamics simulations of the ch28/11-glycan complex, which show that SSEA-4 is stabilized by its terminal sialic acid, unlike SSEA-3, which lacks this sialic acid modification. These high-resolution views of how a glycolipid interacts with an antibody may help to advance a new class of cancer-targeting immunotherapy.

PubMed: 31831622
DOI: 10.1074/jbc.RA119.011518

実験手法

X-RAY DIFFRACTION (2.5 Å)