9PTT
Protein Complex(local refinement)
Summary for 9PTT
| Entry DOI | 10.2210/pdb9ptt/pdb |
| EMDB information | 71846 |
| Descriptor | Frizzled-4, Tetraspanin-12, Norrin, ... (6 entities in total) |
| Functional Keywords | wnt signaling; norrin-fzd4-tspan12-lrp5 complex; designed binder; cryo-em; membrane protein., signaling protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 10 |
| Total formula weight | 612404.61 |
| Authors | |
| Primary citation | Hu, Q.,Li, D.,Long, T.,Sun, Y.,Junge, H.J.,Schmiege, P.,Li, X. Architecture of the Norrin signaling complex and structure-guided surrogate design. Nat.Struct.Mol.Biol., 2026 Cited by PubMed Abstract: Norrin binds Frizzled 4 (FZD), tetraspanin 12 (TSPAN12) and low-density lipoprotein receptor-related protein 5 (LRP5) to regulate angiogenesis and the integrity of the blood-brain barrier and inner blood-retina barrier (BRB). Aberrant Norrin signal causes retinopathies, BRB defects and deafness. Therapeutic mimetics of Norrin are currently in clinical trials for eye diseases. To characterize the mechanism of Norrin signal biogenesis, we determined the structure of a Norrin-FZD-TSPAN12-LRP5 signaling complex using a de novo designed FZD binder as a 'protein glue'. Our structure shows that two curved Norrin homodimers bridge two FZD-TSPAN12 heterodimers. LRP5 simultaneously interacts with TSPAN12 and two Norrin homodimers, positioning the cytosolic FZD and LRP5 tails for signal activation. On the basis of our findings, we designed FZD-LRP5 bispecific binders that act as Norrin surrogates. Our signaling assays showed that oligomerization of the Norrin surrogate enhances signaling potency. Thus, this work reveals how the Norrin signal is generated and may assist in the development of Norrin/Wnt mimetics. PubMed: 42907587DOI: 10.1038/s41594-026-01909-1 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.6 Å) |
Structure validation
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