9E9G

Heligmosomoides polygyrus TGF-beta Mimic 6 Domain 3 (TGM6-D3) Bound to Human TGF-beta Type II Receptor Extracellular Domain

Replaces:  8GDT

Summary for 9E9G

• Entry DOI: 10.2210/pdb9e9g/pdb
• Descriptor: TGF-beta receptor type-2, Transforming growth factor beta mimic 6, GLYCEROL, ... (7 entities in total)
• Functional Keywords: inhibitor, complex, tgf-beta mimic, hptgm, tgm6, tgm6-d3, tgf-beta, tbrii, fibroblasts, immunosuppressant
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 24966.20

Authors

White, S.E.,Schwartze, T.A.,Hinck, A.P. (deposition date: 2024-11-08, release date: 2025-01-22, Last modification date: 2025-08-06)

Primary citation

White, S.E.,Schwartze, T.A.,Mukundan, A.,Schoenherr, C.,Singh, S.P.,van Dinther, M.,Cunningham, K.T.,White, M.P.J.,Campion, T.,Pritchard, J.,Hinck, C.S.,Ten Dijke, P.,Inman, G.J.,Maizels, R.M.,Hinck, A.P.
TGM6 is a helminth secretory product that mimics TGF-beta binding to TGFBR2 to antagonize signaling in fibroblasts.
Nat Commun, 16:1847-1847, 2025

PubMed Abstract: TGM6 is a natural antagonist of mammalian TGF-β signaling produced by the murine helminth parasite Heligmosomoides polygyrus. It differs from the previously described agonist, TGM1 (TGF-β Mimic-1), in that it lacks domains 1/2 that bind TGFBR1. It nonetheless retains TGFBR2 binding through domain 3 and potently inhibits TGF-β signaling in fibroblasts and epithelial cells, but does not inhibit TGF-β signaling in T cells, consistent with divergent domains 4/5 and an altered co-receptor binding preference. The crystal structure of TGM6 bound to TGFBR2 reveals an interface remarkably similar to that of TGF-β with TGFBR2. Thus, TGM6 has adapted its structure to mimic TGF-β, while engaging a distinct co-receptor to direct antagonism to fibroblasts and epithelial cells. The co-expression of TGM6, along with immunosuppressive TGMs that activate the TGF-β pathway, may minimize fibrotic damage to the host as the parasite progresses through its life cycle from the intestinal lumen to submucosa and back again. The co-receptor-dependent targeting of TGFBR2 by the parasite provides a template for the development of therapies for targeting the cancer- and fibrosis-promoting activities of the TGF-βs in humans.

PubMed: 39984487
DOI: 10.1038/s41467-025-56954-z

Experimental method

X-RAY DIFFRACTION (1.4 Å)