9R18
Structure of Sortilin ECD in complex with TNFa-targeting SORTAC
This is a non-PDB format compatible entry.
Summary for 9R18
| Entry DOI | 10.2210/pdb9r18/pdb |
| Descriptor | Sortilin, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total) |
| Functional Keywords | lysosome sorting receptor, targeted protein degradation, sortilin-based lysosome targeting chimeras (sortacs), protein binding |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 87083.43 |
| Authors | |
| Primary citation | Gustafsen, C.,Vilstrup, J.,Kristensen, M.,Koster, D.,Lende, J.,Larsen, C.,Simonsen, A.,Graversen, A.,Olsen, D.,Pallesen, L.T.,Vaegter, C.B.,Kresse, J.C.,Schou, M.,Weyer, K.,Etzerodt, A.,Palmfeldt, J.,Kaas, M.,Qureshi, O.,Harrison, N.,Cowley, J.,Barnes, N.,Galland, F.,Naquet, P.,Mazarakis, S.M.M.,Greve, D.,Quattropani, A.,Glossop, P.,Whitlock, G.,Jensen, K.T.,Nielsen, S.F.,Madsen, P.,Glerup, S. Reshaping the progranulin/sortilin interaction for targeted degradation of extracellular proteins. Cell Chem Biol, 2026 Cited by PubMed Abstract: Targeted protein degradation (TPD) using PROteolysis TArgeting Chimeras (PROTACs) is a powerful therapeutic strategy for degrading difficult-to-drug cytosolic proteins in the proteasome. Here, we present a strategy for extracellular TPD by reshaping the interaction between the lysosome sorting receptor sortilin and its ligand progranulin for engineering SORtilin-based lysosome TArgeting Chimeras (SORTACs). SORTACs induce ternary complex formation followed by endocytosis and target degradation. SORTAC activity can be genetically encoded, demonstrated by converting an IgG-binding nanobody to an IgG-degrading nanobody or by chemical conjugation, enabling conversion of therapeutic antibodies from binding their target to driving its degradation. Importantly, we generated PROTAC-like small molecule SORTACs with nanomolar range potency against two inflammatory proteins, the cytokine TNFa and the membrane protein vanin-1. Our results demonstrate that SORTACs constitute a modular platform for rapid generation of degraders of extracellular targets and with the potential to have wide impact in drug discovery. PubMed: 41903545DOI: 10.1016/j.chembiol.2026.03.002 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.802 Å) |
Structure validation
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