8REX

CryoEM structure of mouse GARP-lTGFbeta1 in complex with a Fab fragment derived from an activating antibody.

8REX の概要

• エントリーDOI: 10.2210/pdb8rex/pdb
• EMDBエントリー: 19111
• 分子名称: Transforming growth factor beta-1 proprotein, Transforming growth factor beta activator LRRC32, mFab LMT-12, Light Chain, ... (6 entities in total)
• 機能のキーワード: garp, tgf-b1, activation, treg, immune system, antibody
• 由来する生物種: Mus musculus (house mouse); 詳細
• タンパク質・核酸の鎖数: 9
• 化学式量合計: 354609.07

構造登録者

Felix, J.,Lambert, F.,Marien, L.,van der Woning, B.,Savvides, S.N.,Lucas, S. (登録日: 2023-12-12, 公開日: 2025-06-25, 最終更新日: 2025-10-08)

主引用文献

Lambert, F.,Felix, J.,Wautier, S.,Dupre, E.,Jamez, M.,Michiels, C.,Gaignage, M.,Marien, L.,Lesage, M.,van der Woning, B.,Savvides, S.N.,Lucas, S.
Antibody-mediated TGF-beta 1 activation for the treatment of diseases caused by deleterious T cell activity.
Cell Rep, 44:116061-116061, 2025

PubMed Abstract: Transforming growth factor β1 (TGF-β1) is an immunosuppressive cytokine produced as a latent homodimer, in which mature TGF-β1 is encapsulated and kept inactive by the latency-associated peptide (LAP). The transmembrane protein GARP presents latent TGF-β1 on the surface of regulatory T cells (Tregs) to enable activation and release of mature TGF-β1 by integrins. Here, we derived monoclonal antibodies (mAbs) that activate latent TGF-β1 anchored on cells by a transmembrane protein. Biochemical and structural studies by electron cryo-microscopy (cryo-EM) reveal that such mAb-mediated activation requires bivalent binding close to the LAP dimerization interface and crosslinking of two membrane-bound GARP:TGF-β1 complexes on the same cell or across different cells. Administration of mAbs to mice with graft versus host disease reduced disease severity and increased survival. The therapeutic effect required Tregs. Collectively, our findings demonstrate that activation of membrane-bound TGF-β1 in vivo is achievable with mAbs, introducing new immunotherapeutic options for allo- or autoimmune diseases characterized by deleterious T cell activity insufficiently controlled by Tregs.

PubMed: 40742810
DOI: 10.1016/j.celrep.2025.116061

実験手法

ELECTRON MICROSCOPY (3 Å)