OCA at 12:43, 1 February 2024

OCA — Thu, 01 Feb 2024 12:43:26 GMT

←Older revision		Revision as of 12:43, 1 February 2024
Line 1:		Line 1:

	==X-ray structure of furin in complex with the guanylhydrazone-based inhibitor 4 (mi359)==		==X-ray structure of furin in complex with the guanylhydrazone-based inhibitor 4 (mi359)==
-	<StructureSection load='7o22' size='340' side='right'caption='[[7o22]]' scene=''>	+	<StructureSection load='7o22' size='340' side='right'caption='[[7o22]], [[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=7O22 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7O22 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7o22]] 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=7O22 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7O22 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=7o22 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7o22 OCA], [https://pdbe.org/7o22 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7o22 RCSB], [https://www.ebi.ac.uk/pdbsum/7o22 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7o22 ProSAT]</span></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]] 1.8Å</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=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=UYW:[azanyl-[(2E)-2-[[2-[(4-chlorophenyl)methoxy]phenyl]methylidene]hydrazinyl]methylidene]azanium'>UYW</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=7o22 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7o22 OCA], [https://pdbe.org/7o22 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7o22 RCSB], [https://www.ebi.ac.uk/pdbsum/7o22 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7o22 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 ==
		+	The pro-protein convertase furin is a highly specific serine protease involved in the proteolytic maturation of many proteins in the secretory pathway. It also activates surface proteins of many viruses including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Furin inhibitors effectively suppress viral replication and thus are promising antiviral therapeutics with broad application potential. Polybasic substrate-like ligands typically trigger conformational changes shifting furin's active site cleft from the OFF-state to the ON-state. Here, we solved the X-ray structures of furin in complex with four different arginine mimetic compounds with reduced basicity. These guanylhydrazone-based inhibitor complexes showed for the first time an active site-directed binding mode to furin's OFF-state conformation. The compounds undergo unique interactions within the S1 pocket, largely different compared to substrate-like ligands. A second binding site was identified at the S4/S5 pocket of furin. Crystallography-based titration experiments confirmed the S1 site as the primary binding pocket. We also tested the proprotein convertases PC5/6 and PC7 for inhibition by guanylhydrazones and found an up to 7-fold lower potency for PC7. Interestingly, the observed differences in the Ki values correlated with the sequence conservation of the PCs at the allosteric sodium binding site. Therefore, OFF-state-specific targeting of furin can serve as a valuable strategy for structure-based development of PC-selective small-molecule inhibitors.
		+
		+	OFF-State-Specific Inhibition of the Proprotein Convertase Furin.,Dahms SO, Haider T, Klebe G, Steinmetzer T, Brandstetter H ACS Chem Biol. 2021 Sep 17;16(9):1692-1700. doi: 10.1021/acschembio.1c00411. Epub, 2021 Aug 20. PMID:34415722<ref>PMID:34415722</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7o22" 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]]

OCA at 09:04, 29 September 2021

OCA — Wed, 29 Sep 2021 09:04:39 GMT

←Older revision		Revision as of 09:04, 29 September 2021
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 7o22 ~~is ON HOLD until Paper Publication~~	+	==X-ray structure of furin in complex with the guanylhydrazone-based inhibitor 4 (mi359)==
-		+	<StructureSection load='7o22' size='340' side='right'caption='[[7o22]]' scene=''>
-	~~Authors~~:	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7O22 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7O22 FirstGlance]. <br>
-	~~Description~~:	+	</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=7o22 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7o22 OCA], [https://pdbe.org/7o22 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7o22 RCSB], [https://www.ebi.ac.uk/pdbsum/7o22 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7o22 ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Brandstetter H]]
		+	[[Category: Dahms SO]]

OCA at 06:34, 21 April 2021

OCA — Wed, 21 Apr 2021 06:34:53 GMT

←Older revision		Revision as of 06:34, 21 April 2021
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7o22 is ON HOLD	+	The entry 7o22 is ON HOLD until Paper Publication

	Authors:		Authors:

OCA: Protected "7o22" [edit=sysop:move=sysop]

OCA — Wed, 07 Apr 2021 04:53:51 GMT

Protected "7o22" [edit=sysop:move=sysop]

←Older revision

Revision as of 04:53, 7 April 2021

OCA: New page: '''Unreleased structure''' The entry 7o22 is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Wed, 07 Apr 2021 04:53:49 GMT

New page: '''Unreleased structure''' The entry 7o22 is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 7o22 is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]

7o22 - Revision history

OCA at 12:43, 1 February 2024

OCA at 09:04, 29 September 2021

OCA at 06:34, 21 April 2021

OCA: Protected "7o22" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 7o22 is ON HOLD Authors: Description: Category: Unreleased Structures