8REX
CryoEM structure of mouse GARP-lTGFbeta1 in complex with a Fab fragment derived from an activating antibody.
Summary for 8REX
| Entry DOI | 10.2210/pdb8rex/pdb |
| EMDB information | 19111 |
| Descriptor | Transforming growth factor beta-1 proprotein, Transforming growth factor beta activator LRRC32, mFab LMT-12, Light Chain, ... (6 entities in total) |
| Functional Keywords | garp, tgf-b1, activation, treg, immune system, antibody |
| Biological source | Mus musculus (house mouse) More |
| Total number of polymer chains | 9 |
| Total formula weight | 354609.07 |
| Authors | Felix, J.,Lambert, F.,Marien, L.,van der Woning, B.,Savvides, S.N.,Lucas, S. (deposition date: 2023-12-12, release date: 2025-06-25, Last modification date: 2025-10-08) |
| Primary citation | 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 Cited by 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: 40742810DOI: 10.1016/j.celrep.2025.116061 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3 Å) |
Structure validation
Download full validation report
