9MVX

Crystal structure of knob-in-hole immunoglobulin G1 Fc heterodimer with P374A

9MVX の概要

• エントリーDOI: 10.2210/pdb9mvx/pdb
• 分子名称: Isoform 1 of Immunoglobulin heavy constant gamma 1 HC1 (Hole), Isoform 1 of Immunoglobulin heavy constant gamma 1 HC2 (Knob), 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[2-acetamido-2-deoxy-beta-D-glucopyranose-(1-2)-alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• 機能のキーワード: human fc fragment, immune response, immune system, knob, hole, knob-in-hole, kih, proala, proline-to-alanine, bispecific antibody, bsab, bsigg, cis-peptide
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 52954.36

構造登録者

Choi, W.S.,Tilegenova, C.,Are, M.,Zwolak, A.,Shaffer, P.,Sharma, S. (登録日: 2025-01-16, 公開日: 2025-11-12)

主引用文献

Tilegenova, C.,Liu, T.,Zhao, Q.,Are, M.,Zhao, Y.,Choi, W.S.,Bhaumik, A.,Steele, R.,Manieri, N.A.,Turegun, B.,Ni, A.,Cardoso, R.M.F.,Shaffer, P.,Clark, D.,Ernst, R.,Li, W.,Taylor, T.,Swaminathan, S.K.,Ramaraju, B.,Liaw, K.,Jacobs, S.A.,Sharma, S.,Cheung, W.C.,Zwolak, A.
Folding-mediated secretion of pure bispecific antibodies.
Nat.Biotechnol., 2025

PubMed Abstract: Bispecific antibodies (bsAbs) can enable therapeutic mechanisms, such as dual antigen targeting or receptor agonism, that are impossible using monoclonal antibodies. BsAbs with IgG-like format (bsIgG) are comprised of two unique heavy chains, each having a cognate light chain. Co-expression of these four unique polypeptides often leads to several mispaired species that are difficult to separate from the target bsIgG due to their similar biophysical properties. Here we describe a set of mutations called ProAla that exploit a the unfolded protein response pathway of cells. ProAla heavy chains are engineered with higher folding energy barriers such that only the cognate light and heavy chains can induce folding, chaperone release and secretion. The structures of the ProAla Fab and Fc regions are identical in structure to normal antibodies, enabling maintenance of half-life and function. Mispaired polypeptides fail to secrete from the cell due to enhanced interaction with the endoplasmic reticulum chaperone BiP, resulting in increased purity of secreted bsIgGs.

PubMed: 41057658
DOI: 10.1038/s41587-025-02842-2

実験手法

X-RAY DIFFRACTION (1.84 Å)