9FID
X-ray structure of furin (PCSK3) in complex with the PC1/3 (PCSK1) prodomain mutant R78K,R80A
Summary for 9FID
| Entry DOI | 10.2210/pdb9fid/pdb |
| Descriptor | Furin, Neuroendocrine convertase 1, CALCIUM ION, ... (5 entities in total) |
| Functional Keywords | furin, proprotein convertase subtilisin/kexin type 3, pcsk3, pcsk1, prodomain, complex, activation, hydrolase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 6 |
| Total formula weight | 190683.28 |
| Authors | |
| Primary citation | Klaushofer, R.,Bloch, K.,Eder, L.S.,Marzaro, S.,Schubert, M.,Bottcher-Friebertshauser, E.,Brandstetter, H.,Dahms, S.O. Structural insights into proprotein convertase activation facilitate the engineering of highly specific furin inhibitors. Nat Commun, 16:8206-8206, 2025 Cited by PubMed Abstract: Proprotein convertases (PCs), including furin and PC1/3 among nine mammalian homologues, mediate the maturation of numerous secreted substrates by proteolytic cleavage. Disbalance of PC activity is associated with diseases like cancer, fibrosis, neurodegeneration and infections. Therefore, PCs are promising drug targets for the treatment of many diseases. However, the highly conserved active site of PCs complicates the development of specific inhibitors. Here we investigate the activation mechanism of PCs using X-ray crystallography and biochemical methods. The structure-based optimization of the multibasic secondary cleavage site loop not only prevents the prodomain's proteolytic cleavage but also increases its inhibition of furin. Combination of cleavage-resistant PC1/3-prodomain variants and a furin-specific nanobody in fusion proteins reveal very potent inhibitors (K = 1.2 pM) with a more than 25,000-fold higher specificity for furin compared to the closely related PC-member PCSK5. Such fusion proteins effectively suppress the replication of a furin-dependent H7N7-influenza virus in cell-based assays. PubMed: 40897699DOI: 10.1038/s41467-025-63479-y PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.4 Å) |
Structure validation
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