- EMDB-19111: CryoEM structure of mouse GARP-lTGFbeta1 in complex with a Fab fr... -
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基本情報
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データベース: EMDB / ID: EMD-19111
タイトル
CryoEM structure of mouse GARP-lTGFbeta1 in complex with a Fab fragment derived from an activating antibody.
マップデータ
Main map: Sharpened map of mouse GARP-lTGFbeta1 in complex with Fab LMT-12, used for model refinement. Additional map: DeepEMhancer sharpened map, used for model building and map visualization.
試料
複合体: mouse GAPR-lTGFbeta1 in complex with Fab LMT-12.
Fonds National de la Recherche Scientifique (FNRS)
PDR / T.0145.21
ベルギー
Fonds National de la Recherche Scientifique (FNRS)
WELBIO / CR2019A-02R
ベルギー
Other private
Salus Sanguinis
引用
ジャーナル: Cell Rep / 年: 2025 タイトル: Antibody-mediated TGF-β1 activation for the treatment of diseases caused by deleterious T cell activity. 著者: Fanny Lambert / Jan Felix / Séverine Wautier / Emilie Dupré / Mathieu Jamez / Camille Michiels / Mélanie Gaignage / Lore Mariën / Manon Lesage / Bas van der Woning / Savvas N Savvides / Sophie Lucas / 要旨: 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 ...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.
ダウンロード / ファイル: emd_19111.map.gz / 形式: CCP4 / 大きさ: 325 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
注釈
Main map: Sharpened map of mouse GARP-lTGFbeta1 in complex with Fab LMT-12, used for model refinement. Additional map: DeepEMhancer sharpened map, used for model building and map visualization.
フィルム・検出器のモデル: GATAN K3 (6k x 4k) / 撮影したグリッド数: 1 / 実像数: 13898 / 平均露光時間: 3.37 sec. / 平均電子線量: 61.8 e/Å2 詳細: A total of 6605 untilted movies were collected followed by 3508 movies at 20 degree tilt.