9fic

High-resolution X-ray structure of human PC1/3 (PCSK1) prodomain R77A,R80A,R81A triple-mutant

spinqualitylabelsall models 9fic, resolution 1.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9fic is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.3Å Ligands: NA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease NEC1_HUMAN Obesity due to prohormone convertase I deficiency. The disease is caused by variants affecting the gene represented in this entry. Function NEC1_HUMAN Involved in the processing of hormone and other protein precursors at sites comprised of pairs of basic amino acid residues. Substrates include POMC, renin, enkephalin, dynorphin, somatostatin, insulin and AGRP.[UniProtKB:P63239] Publication Abstract from PubMed 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(i) = 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. Structural insights into proprotein convertase activation facilitate the engineering of highly specific furin inhibitors.,Klaushofer R, Bloch K, Eder LS, Marzaro S, Schubert M, Bottcher-Friebertshauser E, Brandstetter H, Dahms SO Nat Commun. 2025 Sep 2;16(1):8206. doi: 10.1038/s41467-025-63479-y. PMID:40897699 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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