View source for 9fid


==X-ray structure of furin (PCSK3) in complex with the PC1/3 (PCSK1) prodomain mutant R78K,R80A==
<StructureSection load='9fid' size='340' side='right'caption='[[9fid]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9fid]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9FID OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9FID FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.4&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9fid FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9fid OCA], [https://pdbe.org/9fid PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9fid RCSB], [https://www.ebi.ac.uk/pdbsum/9fid PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9fid ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/FURIN_HUMAN FURIN_HUMAN] Furin is likely to represent the ubiquitous endoprotease activity within constitutive secretory pathways and capable of cleavage at the RX(K/R)R consensus motif.<ref>PMID:7690548</ref> 
<div style="background-color:#fffaf0;">
== 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<ref>PMID:40897699</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9fid" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Brandstetter H]]
[[Category: Dahms SO]]