5mkr - Revision history

OCA at 07:26, 1 May 2024

2024-05-01T07:26:19Z

←Older revision		Revision as of 07:26, 1 May 2024
Line 10:		Line 10:
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/HS71A_HUMAN HS71A_HUMAN] In cooperation with other chaperones, Hsp70s stabilize preexistent proteins against aggregation and mediate the folding of newly translated polypeptides in the cytosol as well as within organelles. These chaperones participate in all these processes through their ability to recognize nonnative conformations of other proteins. They bind extended peptide segments with a net hydrophobic character exposed by polypeptides during translation and membrane translocation, or following stress-induced damage. In case of rotavirus A infection, serves as a post-attachment receptor for the virus to facilitate entry into the cell. Essential for STUB1-mediated ubiquitination and degradation of FOXP3 in regulatory T-cells (Treg) during inflammation (PubMed:23973223).<ref>PMID:16537599</ref> <ref>PMID:22528486</ref> <ref>PMID:23973223</ref>		[https://www.uniprot.org/uniprot/HS71A_HUMAN HS71A_HUMAN] In cooperation with other chaperones, Hsp70s stabilize preexistent proteins against aggregation and mediate the folding of newly translated polypeptides in the cytosol as well as within organelles. These chaperones participate in all these processes through their ability to recognize nonnative conformations of other proteins. They bind extended peptide segments with a net hydrophobic character exposed by polypeptides during translation and membrane translocation, or following stress-induced damage. In case of rotavirus A infection, serves as a post-attachment receptor for the virus to facilitate entry into the cell. Essential for STUB1-mediated ubiquitination and degradation of FOXP3 in regulatory T-cells (Treg) during inflammation (PubMed:23973223).<ref>PMID:16537599</ref> <ref>PMID:22528486</ref> <ref>PMID:23973223</ref>
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	The stress-inducible molecular chaperone, HSP72, is an important therapeutic target in oncology, but inhibiting this protein with small molecules has proven particularly challenging. Validating HSP72 inhibitors in cells is difficult owing to competition with the high affinity and abundance of its endogenous nucleotide substrates. We hypothesized this could be overcome using a cysteine-targeted irreversible inhibitor. Using rational design, we adapted a validated 8-N-benzyladenosine ligand for covalent bond formation and confirmed targeted irreversible inhibition. However, no cysteine in the protein was modified; instead, we demonstrate that lysine-56 is the key nucleophilic residue. Targeting this lysine could lead to a new design paradigm for HSP72 chemical probes and drugs.
-
-	An Irreversible Inhibitor of HSP72 that Unexpectedly Targets Lysine-56.,Pettinger J, Le Bihan YV, Widya M, van Montfort RL, Jones K, Cheeseman MD Angew Chem Int Ed Engl. 2017 Feb 22. doi: 10.1002/anie.201611907. PMID:28225177<ref>PMID:28225177</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 5mkr" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==

OCA at 18:48, 1 November 2023

2023-11-01T18:48:27Z

←Older revision		Revision as of 18:48, 1 November 2023
Line 3:		Line 3:
	<StructureSection load='5mkr' size='340' side='right'caption='[[5mkr]], [[Resolution\|resolution]] 1.87Å' scene=''>		<StructureSection load='5mkr' size='340' side='right'caption='[[5mkr]], [[Resolution\|resolution]] 1.87Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5mkr]] is a 1 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MKR OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=5MKR FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5mkr]] 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=5MKR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5MKR FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FLC:CITRATE+ANION'>FLC</scene>, <scene name='pdbligand=TI8:3-[(2~{R},3~{S},4~{R},5~{R})-5-[6-AZANYL-8-[(4-CHLOROPHENYL)METHYLAMINO]PURIN-9-YL]-3,4-BIS(OXIDANYL)OXOLAN-2-YL]PROPYL+PROP-2-ENOATE'>TI8</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]] 1.87Å</td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">HSPA1A, HSPA1, HSX70 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])~~</td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FLC:CITRATE+ANION'>FLC</scene>, <scene name='pdbligand=TI8:3-[(2~{R},3~{S},4~{R},5~{R})-5-[6-AZANYL-8-[(4-CHLOROPHENYL)METHYLAMINO]PURIN-9-YL]-3,4-BIS(OXIDANYL)OXOLAN-2-YL]PROPYL+PROP-2-ENOATE'>TI8</scene></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=5mkr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mkr OCA], [~~http~~://pdbe.org/5mkr PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5mkr RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5mkr PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5mkr 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=5mkr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mkr OCA], [https://pdbe.org/5mkr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5mkr RCSB], [https://www.ebi.ac.uk/pdbsum/5mkr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5mkr ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/HS71A_HUMAN HS71A_HUMAN]] In cooperation with other chaperones, Hsp70s stabilize preexistent proteins against aggregation and mediate the folding of newly translated polypeptides in the cytosol as well as within organelles. These chaperones participate in all these processes through their ability to recognize nonnative conformations of other proteins. They bind extended peptide segments with a net hydrophobic character exposed by polypeptides during translation and membrane translocation, or following stress-induced damage. In case of rotavirus A infection, serves as a post-attachment receptor for the virus to facilitate entry into the cell. Essential for STUB1-mediated ubiquitination and degradation of FOXP3 in regulatory T-cells (Treg) during inflammation (PubMed:23973223).<ref>PMID:16537599</ref> <ref>PMID:22528486</ref> <ref>PMID:23973223</ref>	+	[https://www.uniprot.org/uniprot/HS71A_HUMAN HS71A_HUMAN] In cooperation with other chaperones, Hsp70s stabilize preexistent proteins against aggregation and mediate the folding of newly translated polypeptides in the cytosol as well as within organelles. These chaperones participate in all these processes through their ability to recognize nonnative conformations of other proteins. They bind extended peptide segments with a net hydrophobic character exposed by polypeptides during translation and membrane translocation, or following stress-induced damage. In case of rotavirus A infection, serves as a post-attachment receptor for the virus to facilitate entry into the cell. Essential for STUB1-mediated ubiquitination and degradation of FOXP3 in regulatory T-cells (Treg) during inflammation (PubMed:23973223).<ref>PMID:16537599</ref> <ref>PMID:22528486</ref> <ref>PMID:23973223</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 26:		Line 26:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Bihan, Y V.Le]]~~	+	[[Category: Cronin N]]
-	[[Category: Cronin, N]]	+	[[Category: Le Bihan Y-V]]
-	[[Category: ~~Montfort, R L.M Van~~]]	+	[[Category: Pettinger J]]
-	[[Category: Pettinger, J]]	+	[[Category: Van Montfort RLM]]
-	[[Category: ~~Westwood, I M~~]]	+	[[Category: Westwood IM]]
-	[[Category: ~~Chaperone]]~~	+
-	~~[[Category: Irreversible inhibitor]]~~	+
-	~~[[Category: Lysine modification~~]]	+

OCA at 07:22, 19 August 2020

2020-08-19T07:22:08Z

←Older revision		Revision as of 07:22, 19 August 2020
Line 1:		Line 1:

	==HSP72-NBD bound to compound TCI 8 - Tyr15 in up-conformation==		==HSP72-NBD bound to compound TCI 8 - Tyr15 in up-conformation==
-	<StructureSection load='5mkr' size='340' side='right' caption='[[5mkr]], [[Resolution\|resolution]] 1.87Å' scene=''>	+	<StructureSection load='5mkr' size='340' side='right'caption='[[5mkr]], [[Resolution\|resolution]] 1.87Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5mkr]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MKR OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5MKR FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5mkr]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MKR OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5MKR FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FLC:CITRATE+ANION'>FLC</scene>, <scene name='pdbligand=TI8:3-[(2~{R},3~{S},4~{R},5~{R})-5-[6-AZANYL-8-[(4-CHLOROPHENYL)METHYLAMINO]PURIN-9-YL]-3,4-BIS(OXIDANYL)OXOLAN-2-YL]PROPYL+PROP-2-ENOATE'>TI8</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FLC:CITRATE+ANION'>FLC</scene>, <scene name='pdbligand=TI8:3-[(2~{R},3~{S},4~{R},5~{R})-5-[6-AZANYL-8-[(4-CHLOROPHENYL)METHYLAMINO]PURIN-9-YL]-3,4-BIS(OXIDANYL)OXOLAN-2-YL]PROPYL+PROP-2-ENOATE'>TI8</scene></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=5mkr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mkr OCA], [http://pdbe.org/5mkr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mkr RCSB], [http://www.ebi.ac.uk/pdbsum/5mkr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mkr ProSAT]</span></td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">HSPA1A, HSPA1, HSX70 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5mkr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mkr OCA], [http://pdbe.org/5mkr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mkr RCSB], [http://www.ebi.ac.uk/pdbsum/5mkr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mkr ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 18:		Line 19:
	</div>		</div>
	<div class="pdbe-citations 5mkr" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5mkr" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Heat Shock Protein structures\|Heat Shock Protein structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Bihan, Y V.Le]]		[[Category: Bihan, Y V.Le]]
	[[Category: Cronin, N]]		[[Category: Cronin, N]]

OCA at 09:38, 11 March 2017

2017-03-11T09:38:27Z

←Older revision		Revision as of 09:38, 11 March 2017
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 5mkr is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==HSP72-NBD bound to compound TCI 8 - Tyr15 in up-conformation==
		+	<StructureSection load='5mkr' size='340' side='right' caption='[[5mkr]], [[Resolution\|resolution]] 1.87Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5mkr]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MKR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5MKR FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FLC:CITRATE+ANION'>FLC</scene>, <scene name='pdbligand=TI8:3-[(2~{R},3~{S},4~{R},5~{R})-5-[6-AZANYL-8-[(4-CHLOROPHENYL)METHYLAMINO]PURIN-9-YL]-3,4-BIS(OXIDANYL)OXOLAN-2-YL]PROPYL+PROP-2-ENOATE'>TI8</scene></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=5mkr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mkr OCA], [http://pdbe.org/5mkr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mkr RCSB], [http://www.ebi.ac.uk/pdbsum/5mkr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mkr ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/HS71A_HUMAN HS71A_HUMAN]] In cooperation with other chaperones, Hsp70s stabilize preexistent proteins against aggregation and mediate the folding of newly translated polypeptides in the cytosol as well as within organelles. These chaperones participate in all these processes through their ability to recognize nonnative conformations of other proteins. They bind extended peptide segments with a net hydrophobic character exposed by polypeptides during translation and membrane translocation, or following stress-induced damage. In case of rotavirus A infection, serves as a post-attachment receptor for the virus to facilitate entry into the cell. Essential for STUB1-mediated ubiquitination and degradation of FOXP3 in regulatory T-cells (Treg) during inflammation (PubMed:23973223).<ref>PMID:16537599</ref> <ref>PMID:22528486</ref> <ref>PMID:23973223</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The stress-inducible molecular chaperone, HSP72, is an important therapeutic target in oncology, but inhibiting this protein with small molecules has proven particularly challenging. Validating HSP72 inhibitors in cells is difficult owing to competition with the high affinity and abundance of its endogenous nucleotide substrates. We hypothesized this could be overcome using a cysteine-targeted irreversible inhibitor. Using rational design, we adapted a validated 8-N-benzyladenosine ligand for covalent bond formation and confirmed targeted irreversible inhibition. However, no cysteine in the protein was modified; instead, we demonstrate that lysine-56 is the key nucleophilic residue. Targeting this lysine could lead to a new design paradigm for HSP72 chemical probes and drugs.

-	~~Authors:~~ Pettinger, J., ~~Westwood~~, I.M., ~~Cronin~~, N., ~~Le Bihan, Y~~.-V.~~, Van Montfort, R~~.L.M.	+	An Irreversible Inhibitor of HSP72 that Unexpectedly Targets Lysine-56.,Pettinger J, Le Bihan YV, Widya M, van Montfort RL, Jones K, Cheeseman MD Angew Chem Int Ed Engl. 2017 Feb 22. doi: 10.1002/anie.201611907. PMID:28225177<ref>PMID:28225177</ref>

-	~~Description: HSP72~~-~~NBD bound to compound TCI 8~~ -~~Tyr15 in up-conformation~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[Category~~: ~~Unreleased Structures]]~~	+	</div>
-	~~[[Category: Pettinger, J]]~~	+	<div class="pdbe-citations 5mkr" style="background-color:#fffaf0;"></div>
-	~~[[Category: Van Montfort, R.L.M]]~~	+	== References ==
-	[[Category: ~~Westwood~~, I.M]]	+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Bihan, Y V.Le]]
	[[Category: Cronin, N]]		[[Category: Cronin, N]]
-	[[Category: ~~Le Bihan~~, Y.-V]]	+	[[Category: Montfort, R L.M Van]]
		+	[[Category: Pettinger, J]]
		+	[[Category: Westwood, I M]]
		+	[[Category: Chaperone]]
		+	[[Category: Irreversible inhibitor]]
		+	[[Category: Lysine modification]]

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

2016-12-15T16:25:30Z

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

←Older revision

Revision as of 16:25, 15 December 2016

OCA: New page: '''Unreleased structure''' The entry 5mkr is ON HOLD until Paper Publication Authors: Pettinger, J., Westwood, I.M., Cronin, N., Le Bihan, Y.-V., Van Montfort, R.L.M. Description: HSP7...

2016-12-15T16:25:28Z

New page: '''Unreleased structure''' The entry 5mkr is ON HOLD until Paper Publication Authors: Pettinger, J., Westwood, I.M., Cronin, N., Le Bihan, Y.-V., Van Montfort, R.L.M. Description: HSP7...

New page

'''Unreleased structure'''

The entry 5mkr is ON HOLD until Paper Publication

Authors: Pettinger, J., Westwood, I.M., Cronin, N., Le Bihan, Y.-V., Van Montfort, R.L.M.

Description: HSP72-NBD bound to compound TCI 8 -Tyr15 in up-conformation
[[Category: Unreleased Structures]]
[[Category: Pettinger, J]]
[[Category: Van Montfort, R.L.M]]
[[Category: Westwood, I.M]]
[[Category: Cronin, N]]
[[Category: Le Bihan, Y.-V]]