7qy1: Difference between revisions
No edit summary |
No edit summary |
||
| Line 3: | Line 3: | ||
<StructureSection load='7qy1' size='340' side='right'caption='[[7qy1]], [[Resolution|resolution]] 1.45Å' scene=''> | <StructureSection load='7qy1' size='340' side='right'caption='[[7qy1]], [[Resolution|resolution]] 1.45Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'> | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7QY1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QY1 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]] 1.45Å</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]] 1.45Å</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=I0W:3-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-ium-1-yl]methyl]-6-[3,5-bis(chloranyl)phenyl]pyridin-2-yl]oxypyridin-2-yl]piperazin-1-ium-1-yl]propanoate'>I0W</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></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=I0W:3-[4-[5-[4-[[4-(acetamidomethyl)piperidin-1-ium-1-yl]methyl]-6-[3,5-bis(chloranyl)phenyl]pyridin-2-yl]oxypyridin-2-yl]piperazin-1-ium-1-yl]propanoate'>I0W</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=7qy1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qy1 OCA], [https://pdbe.org/7qy1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qy1 RCSB], [https://www.ebi.ac.uk/pdbsum/7qy1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qy1 ProSAT]</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=7qy1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qy1 OCA], [https://pdbe.org/7qy1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qy1 RCSB], [https://www.ebi.ac.uk/pdbsum/7qy1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qy1 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 23: | Line 21: | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Brandstetter H]] | [[Category: Brandstetter H]] | ||
[[Category: Dahms SO]] | [[Category: Dahms SO]] | ||
[[Category: Pautsch A]] | [[Category: Pautsch A]] | ||
Latest revision as of 14:25, 23 October 2024
X-ray structure of furin in complex with the dichlorophenylpyridine-based inhibitor 4X-ray structure of furin in complex with the dichlorophenylpyridine-based inhibitor 4
Structural highlights
Publication Abstract from PubMedInhibitors 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|
| ||||||||||||||||||