9YJ4
TGM6-D3 bound to mouse TBRII
Summary for 9YJ4
| Entry DOI | 10.2210/pdb9yj4/pdb |
| Descriptor | Transforming growth factor beta mimic 6, TGF-beta receptor type-2, MAGNESIUM ION, ... (6 entities in total) |
| Functional Keywords | inhibitor, complex, tgf-beta, parasite, molecular mimicry, signaling protein |
| Biological source | Heligmosomoides polygyrus More |
| Total number of polymer chains | 4 |
| Total formula weight | 44500.85 |
| Authors | |
| Primary citation | van Dinther, M.,Schwartze, T.,Zhang, J.,Fan, K.,van der Zon, G.,Power, L.,Hinck, C.S.,Ciancia, C.,Mukundan, A.,Gonzalez-Prieto, R.,van Veelen, P.,Maizels, R.M.,Hinck, A.P.,Ten Dijke, P. Decoding the Mechanism of Action of a Parasite TGF beta Antagonist Inspires the Creation of Cell-Type-Specific TGF beta Modulators. Adv Sci, :e75322-e75322, 2026 Cited by PubMed Abstract: Heligmosomoides polygyrus, a mouse parasite, modulates host immunity by secreting modular transforming growth factor-β (TGFβ) mimics (TGMs). The agonist TGM1 interacts with TGFBR1, TGFBR2, and the co-receptor CD44 through domains D1/2, D3, and D4/5, respectively. In contrast, the antagonist TGM6, which lacks D1/2, but retains TGFBR2 binding through D3, targets different cells compared to TGM1. The TGM6 co-receptor is unknown. Using X-ray crystallography and binding studies, we show that TGM6 preferentially binds mouse TGFBR2 over human TGFBR2, and that this is essential for its antagonistic function. We identified low-density lipoprotein receptor-related protein 1 (LRP1) and betaglycan (TGFBR3) as co-receptors for TGM6. LRP1 enhances TGM6 efficacy and is required for its antagonistic effect by promoting TGFBR2 lysosomal degradation, whereas betaglycan counteracts TGM6 in a TGFBR2-dependent manner. The modular organization of TGMs enabled us to design TGM1/6 chimeras or TGM-D3 fusion with an affibody that recognizes a specific cell-surface receptor, thereby altering cell-type specificity and functionality. Furthermore, we developed a TGFBR2 nanobody that, on its own, has no inhibitory effect but, when fused to a receptor antibody, antagonizes TGFβ by blocking TGFβ receptor interaction in a cell-selective manner. Thus, we designed programmable agents that modulate TGFβ signaling only in co-receptor-expressing cells. PubMed: 42003773DOI: 10.1002/advs.75322 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.52 Å) |
Structure validation
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