This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.

Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.

7lcu

From Proteopedia

(Difference between revisions)

Jump to: navigation, search

Current revision

X-ray structure of Furin bound to BOS-318, a small molecule inhibitor

Structural highlights

7lcu 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 1.24Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.^[1]

Publication Abstract from PubMed

In cystic fibrosis (CF), excessive furin activity plays a critical role in the activation of the epithelial sodium channel (ENaC), dysregulation of which contributes to airway dehydration, ineffective mucociliary clearance (MCC), and mucus obstruction. Here, we report a highly selective, cell-permeable furin inhibitor, BOS-318, that derives selectivity by eliciting the formation of a new, unexpected binding pocket independent of the active site catalytic triad. Using human ex vivo models, BOS-318 showed significant suppression of ENaC, which led to enhanced airway hydration and an approximately 30-fold increase in MCC rate. Furin inhibition also protected ENaC from subsequent activation by neutrophil elastase, a soluble protease dominant in CF airways. Additional therapeutic benefits include protection against epithelial cell death induced by Pseudomonas aeruginosa exotoxin A. Our findings demonstrate the utility of selective furin inhibition as a mutation-agnostic approach that can correct features of CF airway pathophysiology in a manner expected to deliver therapeutic value.

A highly selective, cell-permeable furin inhibitor BOS-318 rescues key features of cystic fibrosis airway disease.,Douglas LEJ, Reihill JA, Ho MWY, Axten JM, Campobasso N, Schneck JL, Rendina AR, Wilcoxen KM, Martin SL Cell Chem Biol. 2022 Jun 16;29(6):947-957.e8. doi:, 10.1016/j.chembiol.2022.02.001. Epub 2022 Feb 23. PMID:35202587^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Takahashi S, Kasai K, Hatsuzawa K, Kitamura N, Misumi Y, Ikehara Y, Murakami K, Nakayama K. A mutation of furin causes the lack of precursor-processing activity in human colon carcinoma LoVo cells. Biochem Biophys Res Commun. 1993 Sep 15;195(2):1019-26. PMID:7690548 doi:http://dx.doi.org/10.1006/bbrc.1993.2146
↑ Douglas LEJ, Reihill JA, Ho MWY, Axten JM, Campobasso N, Schneck JL, Rendina AR, Wilcoxen KM, Martin SL. A highly selective, cell-permeable furin inhibitor BOS-318 rescues key features of cystic fibrosis airway disease. Cell Chem Biol. 2022 Jun 16;29(6):947-957.e8. doi:, 10.1016/j.chembiol.2022.02.001. Epub 2022 Feb 23. PMID:35202587 doi:http://dx.doi.org/10.1016/j.chembiol.2022.02.001

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7lcu"

Categories: Homo sapiens | Large Structures | Campobasso N | Reid R

@@ Line 3: / Line 3: @@
 <StructureSection load='7lcu' size='340' side='right'caption='[[7lcu]], [[Resolution|resolution]] 1.24&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7lcu]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LCU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LCU FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7lcu]] is a 1 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=7LCU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LCU FirstGlance]. <br>
-</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=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=XTA:(1-{[2-(3,5-dichlorophenyl)-6-{[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]oxy}pyridin-4-yl]methyl}piperidin-4-yl)acetic+acid'>XTA</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.24&#8491;</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Furin Furin], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.75 3.4.21.75] </span></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=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=XTA:(1-{[2-(3,5-dichlorophenyl)-6-{[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]oxy}pyridin-4-yl]methyl}piperidin-4-yl)acetic+acid'>XTA</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=7lcu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lcu OCA], [https://pdbe.org/7lcu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lcu RCSB], [https://www.ebi.ac.uk/pdbsum/7lcu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lcu 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>
+[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 ==
@@ Line 23: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Furin]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Campobasso, N]]
+[[Category: Campobasso N]]
-[[Category: Reid, R]]
+[[Category: Reid R]]
-[[Category: Hydrolase-inhibitor complex]]
-[[Category: Inhibitor protease]]

7lcu

From Proteopedia

Current revision

X-ray structure of Furin bound to BOS-318, a small molecule inhibitor

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox