5htg - Revision history

OCA at 12:33, 6 March 2024

OCA — Wed, 06 Mar 2024 12:33:09 GMT

←Older revision		Revision as of 12:33, 6 March 2024
Line 9:		Line 9:
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/FKBP_CANAL FKBP_CANAL]		[https://www.uniprot.org/uniprot/FKBP_CANAL FKBP_CANAL]
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	Invasive fungal infections remain difficult to treat and require novel targeting strategies. The 12-kDa FK506-binding protein (FKBP12) is a ubiquitously expressed peptidyl-prolyl isomerase with considerable homology between fungal pathogens and is thus a prime candidate for future targeting efforts to generate a panfungal strategy. Despite decades of research on FKBPs, their substrates and mechanisms of action remain unclear. Here we describe structural, biochemical, and in vivo analyses of FKBP12s from the pathogenic fungi Candida albicans, Candida glabrata, and Aspergillus fumigatus Strikingly, multiple apo A. fumigatus and C. albicans FKBP12 crystal structures revealed a symmetric, intermolecular interaction involving the deep insertion of an active-site loop proline into the active-site pocket of an adjacent subunit. Such interactions have not been observed in previous FKBP structures. This finding indicates the possibility that this is a self-substrate interaction unique to the A. fumigatus and C. albicans fungal proteins that contain this central proline. Structures obtained with the proline in the cis and trans states provide more data in support of self-catalysis. Moreover, cysteine cross-linking experiments captured the interacting dimer, supporting the idea that it forms in solution. Finally, genetic studies exploring the impact of mutations altering the central proline and an adjacent residue provide evidence that any dimeric state formed in vivo, where FKBP12 concentrations are low, is transient. Taken together, these findings suggest a unique mechanism of self-substrate regulation by fungal FKBP12s, lending further novel understanding of this protein for future drug-targeting efforts. IMPORTANCE: FKBP12 is a cis-trans peptidyl-prolyl isomerase that plays key roles in cellular protein homeostasis. FKBP12s also bind the immunosuppressive drug FK506 to inhibit the phosphatase calcineurin (CaN). CaN is required for virulence of A. fumigatus, C. albicans, C. glabrata, and other deadly fungal pathogens, marking FKBP12 and CaN as potential broad-spectrum drug targets. Here we describe structures of fungal FKBP12s. Multiple apo A. fumigatus and C. albicans FKBP12 structures reveal the insertion of a proline, conspicuously conserved in these proteins, into the active sites of adjacent molecules. This suggests that these proteins might serve as their own substrates. Cysteine disulfide trapping experiments provide support for this self-interaction and hence possible intermolecular catalysis by these enzymes.
-
-	Structures of Pathogenic Fungal FKBP12s Reveal Possible Self-Catalysis Function.,Tonthat NK, Juvvadi PR, Zhang H, Lee SC, Venters R, Spicer L, Steinbach WJ, Heitman J, Schumacher MA MBio. 2016 Apr 26;7(2):e00492-16. doi: 10.1128/mBio.00492-16. PMID:27118592<ref>PMID:27118592</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 5htg" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
	*[[FKBP 3D structures\|FKBP 3D structures]]		*[[FKBP 3D structures\|FKBP 3D structures]]
-	== References ==
-	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>

OCA at 10:53, 16 August 2023

OCA — Wed, 16 Aug 2023 10:53:29 GMT

←Older revision		Revision as of 10:53, 16 August 2023
Line 3:		Line 3:
	<StructureSection load='5htg' size='340' side='right'caption='[[5htg]], [[Resolution\|resolution]] 2.40Å' scene=''>		<StructureSection load='5htg' size='340' side='right'caption='[[5htg]], [[Resolution\|resolution]] 2.40Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5htg]] is a 2 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Canal Canal~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HTG OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=5HTG FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5htg]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Candida_albicans_SC5314 Candida albicans SC5314]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HTG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5HTG FirstGlance]. <br>
-	</td></tr><tr id='~~related~~'><td class="sblockLbl"><b>[[~~Related_structure~~\|~~Related~~:]]</b></td><td class="sblockDat"~~>[[5hw6\|5hw6]], [[5hw7\|5hw7]], [[5hw8\|5hw8]]</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]] 2.4Å</td></tr>
-	~~<tr~~ id~~='gene'><td class~~="~~sblockLbl~~">~~<b>~~[[~~Gene~~\|~~Gene:~~]]~~</b></td><td class="sblockDat">RBP1, RBP11, CaO19~~.~~11186, CaO19.3702, RBP2, RBP12, CaJ7.0299, CaO19.13810, CaO19.6452 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info~~&~~srchmode=5&id=237561 CANAL])</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=5htg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5htg OCA], [https://pdbe.org/5htg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5htg RCSB], [https://www.ebi.ac.uk/pdbsum/5htg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5htg ProSAT]</span></td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Peptidylprolyl_isomerase Peptidylprolyl isomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.2.1.8 5.2.1.8] </span></td></tr>	+
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://proteopedia.org/fgij/fg.htm?mol=5htg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5htg OCA], [~~http~~://pdbe.org/5htg PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5htg RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5htg PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5htg ProSAT]</span></td></tr>	+
	</table>		</table>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/FKBP_CANAL FKBP_CANAL]
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 20:		Line 20:

	==See Also==		==See Also==
-	*[[~~FK506 binding protein~~\|~~FK506 binding protein~~]]	+	*[[FKBP 3D structures\|FKBP 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Canal~~]]	+	[[Category: Candida albicans SC5314]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Peptidylprolyl isomerase]]~~	+	[[Category: Schumacher MA]]
-	[[Category: Schumacher~~, M A]]~~	+
-	~~[[Category: Calcineurin]]~~	+
-	~~[[Category: Fkbp12]]~~	+
-	~~[[Category: Isomerase]]~~	+
-	~~[[Category: Pathogenic fungi~~]]	+

OCA at 08:31, 27 May 2020

OCA — Wed, 27 May 2020 08:31:34 GMT

←Older revision		Revision as of 08:31, 27 May 2020
Line 1:		Line 1:

	==Structure of apo P1 form of Candida albicans FKBP12==		==Structure of apo P1 form of Candida albicans FKBP12==
-	<StructureSection load='5htg' size='340' side='right' caption='[[5htg]], [[Resolution\|resolution]] 2.40Å' scene=''>	+	<StructureSection load='5htg' size='340' side='right'caption='[[5htg]], [[Resolution\|resolution]] 2.40Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5htg]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HTG OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5HTG FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5htg]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Canal Canal]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HTG OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5HTG FirstGlance]. <br>
	</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5hw6\|5hw6]], [[5hw7\|5hw7]], [[5hw8\|5hw8]]</td></tr>		</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5hw6\|5hw6]], [[5hw7\|5hw7]], [[5hw8\|5hw8]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">RBP1, RBP11, CaO19.11186, CaO19.3702, RBP2, RBP12, CaJ7.0299, CaO19.13810, CaO19.6452 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=237561 CANAL])</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Peptidylprolyl_isomerase Peptidylprolyl isomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.2.1.8 5.2.1.8] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Peptidylprolyl_isomerase Peptidylprolyl isomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.2.1.8 5.2.1.8] </span></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5htg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5htg OCA], [http://pdbe.org/5htg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5htg RCSB], [http://www.ebi.ac.uk/pdbsum/5htg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5htg ProSAT]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5htg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5htg OCA], [http://pdbe.org/5htg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5htg RCSB], [http://www.ebi.ac.uk/pdbsum/5htg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5htg ProSAT]</span></td></tr>
	</table>		</table>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
Line 17:		Line 18:
	</div>		</div>
	<div class="pdbe-citations 5htg" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5htg" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[FK506 binding protein\|FK506 binding protein]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Canal]]
		+	[[Category: Large Structures]]
	[[Category: Peptidylprolyl isomerase]]		[[Category: Peptidylprolyl isomerase]]
	[[Category: Schumacher, M A]]		[[Category: Schumacher, M A]]

OCA at 15:19, 14 September 2016

OCA — Wed, 14 Sep 2016 15:19:31 GMT

←Older revision		Revision as of 15:19, 14 September 2016
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 5htg is ~~ON HOLD until Paper~~ Publication	+	==Structure of apo P1 form of Candida albicans FKBP12==
		+	<StructureSection load='5htg' size='340' side='right' caption='[[5htg]], [[Resolution\|resolution]] 2.40Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5htg]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HTG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5HTG FirstGlance]. <br>
		+	</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5hw6\|5hw6]], [[5hw7\|5hw7]], [[5hw8\|5hw8]]</td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Peptidylprolyl_isomerase Peptidylprolyl isomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.2.1.8 5.2.1.8] </span></td></tr>
		+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5htg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5htg OCA], [http://pdbe.org/5htg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5htg RCSB], [http://www.ebi.ac.uk/pdbsum/5htg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5htg ProSAT]</span></td></tr>
		+	</table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Invasive fungal infections remain difficult to treat and require novel targeting strategies. The 12-kDa FK506-binding protein (FKBP12) is a ubiquitously expressed peptidyl-prolyl isomerase with considerable homology between fungal pathogens and is thus a prime candidate for future targeting efforts to generate a panfungal strategy. Despite decades of research on FKBPs, their substrates and mechanisms of action remain unclear. Here we describe structural, biochemical, and in vivo analyses of FKBP12s from the pathogenic fungi Candida albicans, Candida glabrata, and Aspergillus fumigatus Strikingly, multiple apo A. fumigatus and C. albicans FKBP12 crystal structures revealed a symmetric, intermolecular interaction involving the deep insertion of an active-site loop proline into the active-site pocket of an adjacent subunit. Such interactions have not been observed in previous FKBP structures. This finding indicates the possibility that this is a self-substrate interaction unique to the A. fumigatus and C. albicans fungal proteins that contain this central proline. Structures obtained with the proline in the cis and trans states provide more data in support of self-catalysis. Moreover, cysteine cross-linking experiments captured the interacting dimer, supporting the idea that it forms in solution. Finally, genetic studies exploring the impact of mutations altering the central proline and an adjacent residue provide evidence that any dimeric state formed in vivo, where FKBP12 concentrations are low, is transient. Taken together, these findings suggest a unique mechanism of self-substrate regulation by fungal FKBP12s, lending further novel understanding of this protein for future drug-targeting efforts. IMPORTANCE: FKBP12 is a cis-trans peptidyl-prolyl isomerase that plays key roles in cellular protein homeostasis. FKBP12s also bind the immunosuppressive drug FK506 to inhibit the phosphatase calcineurin (CaN). CaN is required for virulence of A. fumigatus, C. albicans, C. glabrata, and other deadly fungal pathogens, marking FKBP12 and CaN as potential broad-spectrum drug targets. Here we describe structures of fungal FKBP12s. Multiple apo A. fumigatus and C. albicans FKBP12 structures reveal the insertion of a proline, conspicuously conserved in these proteins, into the active sites of adjacent molecules. This suggests that these proteins might serve as their own substrates. Cysteine disulfide trapping experiments provide support for this self-interaction and hence possible intermolecular catalysis by these enzymes.

-	~~Authors~~:	+	Structures of Pathogenic Fungal FKBP12s Reveal Possible Self-Catalysis Function.,Tonthat NK, Juvvadi PR, Zhang H, Lee SC, Venters R, Spicer L, Steinbach WJ, Heitman J, Schumacher MA MBio. 2016 Apr 26;7(2):e00492-16. doi: 10.1128/mBio.00492-16. PMID:27118592<ref>PMID:27118592</ref>

-	~~Description~~:	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
		+	<div class="pdbe-citations 5htg" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Peptidylprolyl isomerase]]
		+	[[Category: Schumacher, M A]]
		+	[[Category: Calcineurin]]
		+	[[Category: Fkbp12]]
		+	[[Category: Isomerase]]
		+	[[Category: Pathogenic fungi]]

OCA at 13:53, 15 May 2016

OCA — Sun, 15 May 2016 13:53:54 GMT

←Older revision		Revision as of 13:53, 15 May 2016
Line 3:		Line 3:
	The entry 5htg is ON HOLD until Paper Publication		The entry 5htg is ON HOLD until Paper Publication

-	Authors: ~~Schumacher, M.A.~~	+	Authors:

	Description:		Description:
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
-	[[Category: Schumacher, M.A]]

OCA at 13:00, 2 March 2016

OCA — Wed, 02 Mar 2016 13:00:30 GMT

←Older revision		Revision as of 13:00, 2 March 2016
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5htg is ON HOLD	+	The entry 5htg is ON HOLD until Paper Publication

	Authors: Schumacher, M.A.		Authors: Schumacher, M.A.

OCA: Protected "5htg" [edit=sysop:move=sysop]

OCA — Wed, 03 Feb 2016 14:19:36 GMT

Protected "5htg" [edit=sysop:move=sysop]

←Older revision

Revision as of 14:19, 3 February 2016

OCA: New page: '''Unreleased structure''' The entry 5htg is ON HOLD Authors: Schumacher, M.A. Description: Category: Unreleased Structures Category: Schumacher, M.A

OCA — Wed, 03 Feb 2016 14:19:35 GMT

New page: '''Unreleased structure''' The entry 5htg is ON HOLD Authors: Schumacher, M.A. Description: Category: Unreleased Structures Category: Schumacher, M.A

New page

'''Unreleased structure'''

The entry 5htg is ON HOLD

Authors: Schumacher, M.A.

Description:
[[Category: Unreleased Structures]]
[[Category: Schumacher, M.A]]