7u0u - Revision history

OCA at 17:10, 18 October 2023

OCA — Wed, 18 Oct 2023 17:10:03 GMT

←Older revision		Revision as of 17:10, 18 October 2023
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	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[7u0u]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Aspergillus_fumigatus Aspergillus fumigatus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7U0U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7U0U FirstGlance]. <br>		<table><tr><td colspan='2'>[[7u0u]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Aspergillus_fumigatus Aspergillus fumigatus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7U0U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7U0U FirstGlance]. <br>
-	</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=FK5:8-DEETHYL-8-[BUT-3-ENYL]-ASCOMYCIN'>FK5</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></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]] 1.9Å</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=FK5:8-DEETHYL-8-[BUT-3-ENYL]-ASCOMYCIN'>FK5</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=7u0u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7u0u OCA], [https://pdbe.org/7u0u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7u0u RCSB], [https://www.ebi.ac.uk/pdbsum/7u0u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7u0u 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=7u0u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7u0u OCA], [https://pdbe.org/7u0u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7u0u RCSB], [https://www.ebi.ac.uk/pdbsum/7u0u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7u0u ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/A0A8H4MJX9_ASPFM A0A8H4MJX9_ASPFM]] Regulatory subunit of calcineurin, a calcium-dependent, calmodulin stimulated protein phosphatase. Confers calcium sensitivity.[ARBA:ARBA00023754][[https://www.uniprot.org/uniprot/PP2B_ASPFU PP2B_ASPFU]] Calcium-dependent, calmodulin-stimulated protein phosphatase. This subunit may have a role in the calmodulin activation of calcineurin.	+	[https://www.uniprot.org/uniprot/A0A8H4MJX9_ASPFM A0A8H4MJX9_ASPFM] Regulatory subunit of calcineurin, a calcium-dependent, calmodulin stimulated protein phosphatase. Confers calcium sensitivity.[ARBA:ARBA00023754][https://www.uniprot.org/uniprot/PP2B_ASPFU PP2B_ASPFU] Calcium-dependent, calmodulin-stimulated protein phosphatase. This subunit may have a role in the calmodulin activation of calcineurin.
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
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	</div>		</div>
	<div class="pdbe-citations 7u0u" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 7u0u" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Calcineurin 3D structures\|Calcineurin 3D structures]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 03:18, 8 September 2022

OCA — Thu, 08 Sep 2022 03:18:56 GMT

←Older revision		Revision as of 03:18, 8 September 2022
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-	====	+	==Crystal Structure of a Aspergillus fumigatus Calcineurin A - Calcineurin B fusion bound to FKBP12 and FK-506==
-	<StructureSection load='7u0u' size='340' side='right'caption='[[7u0u]]' scene=''>	+	<StructureSection load='7u0u' size='340' side='right'caption='[[7u0u]], [[Resolution\|resolution]] 1.90Å' 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= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7u0u]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Aspergillus_fumigatus Aspergillus fumigatus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7U0U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7U0U 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=7u0u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7u0u OCA], [https://pdbe.org/7u0u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7u0u RCSB], [https://www.ebi.ac.uk/pdbsum/7u0u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7u0u 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=FK5:8-DEETHYL-8-[BUT-3-ENYL]-ASCOMYCIN'>FK5</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=7u0u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7u0u OCA], [https://pdbe.org/7u0u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7u0u RCSB], [https://www.ebi.ac.uk/pdbsum/7u0u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7u0u ProSAT]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[[https://www.uniprot.org/uniprot/A0A8H4MJX9_ASPFM A0A8H4MJX9_ASPFM]] Regulatory subunit of calcineurin, a calcium-dependent, calmodulin stimulated protein phosphatase. Confers calcium sensitivity.[ARBA:ARBA00023754][[https://www.uniprot.org/uniprot/PP2B_ASPFU PP2B_ASPFU]] Calcium-dependent, calmodulin-stimulated protein phosphatase. This subunit may have a role in the calmodulin activation of calcineurin.
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Calcineurin is an essential virulence factor that is conserved across human fungal pathogens, including Cryptococcus neoformans, Aspergillus fumigatus, and Candida albicans. Although an excellent target for antifungal drug development, the serine-threonine phosphatase activity of calcineurin is conserved in mammals, and inhibition of this activity results in immunosuppression. FK506 (tacrolimus) is a naturally produced macrocyclic compound that inhibits calcineurin by binding to the immunophilin FKBP12. Previously, our fungal calcineurin-FK506-FKBP12 structure-based approaches identified a nonconserved region of FKBP12 that can be exploited for fungus-specific targeting. These studies led to the design of an FK506 analog, APX879, modified at the C-22 position, which was less immunosuppressive yet maintained antifungal activity. We now report high-resolution protein crystal structures of fungal FKBP12 and a human truncated calcineurin-FKBP12 bound to a natural FK506 analog, FK520 (ascomycin). Based on information from these structures and the success of APX879, we synthesized and screened a novel panel of C-22-modified compounds derived from both FK506 and FK520. One compound, JH-FK-05, demonstrates broad-spectrum antifungal activity in vitro and is nonimmunosuppressive in vivo. In murine models of pulmonary and disseminated C. neoformans infection, JH-FK-05 treatment significantly reduced fungal burden and extended animal survival alone and in combination with fluconazole. Furthermore, molecular dynamic simulations performed with JH-FK-05 binding to fungal and human FKBP12 identified additional residues outside the C-22 and C-21 positions that could be modified to generate novel FK506 analogs with improved antifungal activity. IMPORTANCE Due to rising rates of antifungal drug resistance and a limited armamentarium of antifungal treatments, there is a paramount need for novel antifungal drugs to treat systemic fungal infections. Calcineurin has been established as an essential and conserved virulence factor in several fungi, making it an attractive antifungal target. However, due to the immunosuppressive action of calcineurin inhibitors, they have not been successfully utilized clinically for antifungal treatment in humans. Recent availability of crystal structures of fungal calcineurin-bound inhibitor complexes has enabled the structure-guided design of FK506 analogs and led to a breakthrough in the development of a compound with increased fungal specificity. The development of a calcineurin inhibitor with reduced immunosuppressive activity and maintained therapeutic antifungal activity would add a significant tool to the treatment options for these invasive fungal infections with exceedingly high rates of mortality.
		+
		+	Structure-Guided Synthesis of FK506 and FK520 Analogs with Increased Selectivity Exhibit In Vivo Therapeutic Efficacy against Cryptococcus.,Hoy MJ, Park E, Lee H, Lim WY, Cole DC, DeBouver ND, Bobay BG, Pierce PG, Fox D 3rd, Ciofani M, Juvvadi PR, Steinbach W, Hong J, Heitman J mBio. 2022 Jun 28;13(3):e0104922. doi: 10.1128/mbio.01049-22. Epub 2022 May 23. PMID:35604094<ref>PMID:35604094</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7u0u" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Aspergillus fumigatus]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~Z-disk~~]]	+	[[Category: Abendroth J]]
		+	[[Category: DeBouver ND]]
		+	[[Category: Edwards TE]]
		+	[[Category: Fox III D]]
		+	[[Category: Heitman J]]
		+	[[Category: Horanyi PS]]
		+	[[Category: Hoy MJ]]
		+	[[Category: Lorimer DD]]

OCA at 04:53, 3 August 2022

OCA — Wed, 03 Aug 2022 04:53:47 GMT

←Older revision		Revision as of 04:53, 3 August 2022
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 7u0u ~~is ON HOLD until Paper Publication~~	+	====
-		+	<StructureSection load='7u0u' size='340' side='right'caption='[[7u0u]]' scene=''>
-	~~Authors~~:	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= 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=7u0u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7u0u OCA], [https://pdbe.org/7u0u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7u0u RCSB], [https://www.ebi.ac.uk/pdbsum/7u0u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7u0u ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Z-disk]]

OCA at 10:22, 27 April 2022

OCA — Wed, 27 Apr 2022 10:22:00 GMT

←Older revision		Revision as of 10:22, 27 April 2022
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7u0u is ON HOLD	+	The entry 7u0u is ON HOLD until Paper Publication

	Authors:		Authors:

OCA: Protected "7u0u" [edit=sysop:move=sysop]

OCA — Wed, 02 Mar 2022 05:06:39 GMT

Protected "7u0u" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:06, 2 March 2022

OCA: New page: '''Unreleased structure''' The entry 7u0u is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Wed, 02 Mar 2022 05:06:38 GMT

New page: '''Unreleased structure''' The entry 7u0u is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 7u0u is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]