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.
7qxz
From Proteopedia
(Difference between revisions)
| Line 1: | Line 1: | ||
==X-ray structure of furin in complex with the dichlorophenylpyridine-based inhibitor 5== | ==X-ray structure of furin in complex with the dichlorophenylpyridine-based inhibitor 5== | ||
| - | <StructureSection load='7qxz' size='340' side='right'caption='[[7qxz]]' scene=''> | + | <StructureSection load='7qxz' size='340' side='right'caption='[[7qxz]], [[Resolution|resolution]] 1.80Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7QXZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QXZ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7qxz]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7QXZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QXZ FirstGlance]. <br> |
| - | </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=7qxz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qxz OCA], [https://pdbe.org/7qxz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qxz RCSB], [https://www.ebi.ac.uk/pdbsum/7qxz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qxz ProSAT]</span></td></tr> | + | </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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=I0M:2-[(3S)-1-[[2-[3,5-bis(chloranyl)phenyl]-6-[2-(4-methylpiperazin-4-ium-1-yl)pyrimidin-5-yl]oxy-pyridin-4-yl]methyl]pyrrolidin-1-ium-3-yl]oxyethanoic+acid'>I0M</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7qxz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qxz OCA], [https://pdbe.org/7qxz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qxz RCSB], [https://www.ebi.ac.uk/pdbsum/7qxz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qxz ProSAT]</span></td></tr> | ||
</table> | </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 == | ||
| + | Inhibitors of the proprotein convertase furin might serve as broad-spectrum antiviral therapeutics. High cellular potency and antiviral activity against acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been reported for (3,5-dichlorophenyl)pyridine-derived furin inhibitors. Here we characterized the binding mechanism of this inhibitor class using structural, biophysical, and biochemical methods. We established a MALDI-TOF-MS-based furin activity assay, determined IC50 values, and solved X-ray structures of (3,5-dichlorophenyl)pyridine-derived compounds in complex with furin. The inhibitors induced a substantial conformational rearrangement of the active-site cleft by exposing a central buried tryptophan residue. These changes formed an extended hydrophobic surface patch where the 3,5-dichlorophenyl moiety of the inhibitors was inserted into a newly formed binding pocket. Consistent with these structural rearrangements, we observed slow off-rate binding kinetics and strong structural stabilization in surface plasmon resonance and differential scanning fluorimetry experiments, respectively. The discovered furin conformation offers new opportunities for structure-based drug discovery. | ||
| + | |||
| + | Dichlorophenylpyridine-Based Molecules Inhibit Furin through an Induced-Fit Mechanism.,Dahms SO, Schnapp G, Winter M, Buttner FH, Schleputz M, Gnamm C, Pautsch A, Brandstetter H ACS Chem Biol. 2022 Apr 15;17(4):816-821. doi: 10.1021/acschembio.2c00103. Epub, 2022 Apr 4. PMID:35377598<ref>PMID:35377598</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7qxz" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Furin]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Brandstetter H]] | + | [[Category: Brandstetter, H]] |
| - | [[Category: Dahms | + | [[Category: Dahms, S O]] |
| - | [[Category: Pautsch A]] | + | [[Category: Pautsch, A]] |
| + | [[Category: Complex]] | ||
| + | [[Category: Hydrolase]] | ||
| + | [[Category: Inhibitor]] | ||
| + | [[Category: Proprotein convertase]] | ||
| + | [[Category: Protease]] | ||
| + | [[Category: Sars-cov-2]] | ||
Revision as of 03:08, 21 April 2022
X-ray structure of furin in complex with the dichlorophenylpyridine-based inhibitor 5
| |||||||||||
