9FID

X-ray structure of furin (PCSK3) in complex with the PC1/3 (PCSK1) prodomain mutant R78K,R80A

9FID の概要

• エントリーDOI: 10.2210/pdb9fid/pdb
• 分子名称: Furin, Neuroendocrine convertase 1, CALCIUM ION, ... (5 entities in total)
• 機能のキーワード: furin, proprotein convertase subtilisin/kexin type 3, pcsk3, pcsk1, prodomain, complex, activation, hydrolase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 190683.28

構造登録者

Dahms, S.O.,Brandstetter, H. (登録日: 2024-05-29, 公開日: 2025-09-10)

主引用文献

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

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: 40897699
DOI: 10.1038/s41467-025-63479-y

実験手法

X-RAY DIFFRACTION (2.4 Å)