7qy2
From Proteopedia
(Difference between revisions)
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==X-ray structure of furin in complex with the dichlorophenylpyridine-based inhibitor 2== | ==X-ray structure of furin in complex with the dichlorophenylpyridine-based inhibitor 2== | ||
| - | <StructureSection load='7qy2' size='340' side='right'caption='[[7qy2]]' scene=''> | + | <StructureSection load='7qy2' size='340' side='right'caption='[[7qy2]], [[Resolution|resolution]] 1.55Å' 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=7QY2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QY2 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7qy2]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7QY2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QY2 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=7qy2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qy2 OCA], [https://pdbe.org/7qy2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qy2 RCSB], [https://www.ebi.ac.uk/pdbsum/7qy2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qy2 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=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=I0Q:(2R)-4-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-ium-1-yl]methyl]-6-[3,5-bis(chloranyl)phenyl]pyridin-2-yl]oxypyrimidin-2-yl]piperazin-1-ium-1-yl]-2-methyl-butanoate'>I0Q</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=7qy2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qy2 OCA], [https://pdbe.org/7qy2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qy2 RCSB], [https://www.ebi.ac.uk/pdbsum/7qy2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qy2 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 7qy2" 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 11:52, 27 April 2022
X-ray structure of furin in complex with the dichlorophenylpyridine-based inhibitor 2
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