7qxz: Difference between revisions

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<StructureSection load='7qxz' size='340' side='right'caption='[[7qxz]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
<StructureSection load='7qxz' size='340' side='right'caption='[[7qxz]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[7qxz]] 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=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'>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='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8&#8491;</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]] 1.8&#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=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='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='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>
<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&reg;/PubMed&reg;, 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: Homo sapiens]]
[[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 09:07, 17 October 2024

X-ray structure of furin in complex with the dichlorophenylpyridine-based inhibitor 5

7qxz, resolution 1.80Å

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