OCA at 16:05, 18 October 2023

OCA — Wed, 18 Oct 2023 16:05:56 GMT

←Older revision		Revision as of 16:05, 18 October 2023
Line 1:		Line 1:

-	====	+	==PCNA bound to peptide mimetic with linker==
-	<StructureSection load='7m5n' size='340' side='right'caption='[[7m5n]]' scene=''>	+	<StructureSection load='7m5n' size='340' side='right'caption='[[7m5n]], [[Resolution\|resolution]] 3.11Å' 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'>[[7m5n]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7M5N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7M5N 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=7m5n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7m5n OCA], [https://pdbe.org/7m5n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7m5n RCSB], [https://www.ebi.ac.uk/pdbsum/7m5n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7m5n 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]] 3.11Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8VH:1,3-dimethylbenzene'>8VH</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</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=7m5n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7m5n OCA], [https://pdbe.org/7m5n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7m5n RCSB], [https://www.ebi.ac.uk/pdbsum/7m5n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7m5n ProSAT]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/PCNA_HUMAN PCNA_HUMAN] Auxiliary protein of DNA polymerase delta and is involved in the control of eukaryotic DNA replication by increasing the polymerase's processibility during elongation of the leading strand. Induces a robust stimulatory effect on the 3'-5' exonuclease and 3'-phosphodiesterase, but not apurinic-apyrimidinic (AP) endonuclease, APEX2 activities. Has to be loaded onto DNA in order to be able to stimulate APEX2. Plays a key role in DNA damage response (DDR) by being conveniently positioned at the replication fork to coordinate DNA replication with DNA repair and DNA damage tolerance pathways. Acts as a loading platform to recruit DDR proteins that allow completion of DNA replication after DNA damage and promote postreplication repair: Monoubiquitinated PCNA leads to recruitment of translesion (TLS) polymerases, while 'Lys-63'-linked polyubiquitination of PCNA is involved in error-free pathway and employs recombination mechanisms to synthesize across the lesion.<ref>PMID:19443450</ref> <ref>PMID:18719106</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The human sliding clamp protein known as proliferating cell nuclear antigen (PCNA) orchestrates DNA-replication and -repair and as such is an ideal therapeutic target for proliferative diseases, including cancer. Peptides derived from the human p21 protein bind PCNA with high affinity via a 3(10)-helical binding conformation and are known to shut down DNA-replication. Here, we present studies on short analogues of p21 peptides (143-151) conformationally constrained with a covalent linker between i, i + 4 separated cysteine residues at positions 145 and 149 to access peptidomimetics that target PCNA. The resulting macrocycles bind PCNA with K (D) values ranging from 570 nM to 3.86 muM, with the bimane-constrained peptide 7 proving the most potent. Subsequent X-ray crystallography and computational modelling studies of the macrocyclic peptides bound to PCNA indicated only the high-affinity peptide 7 adopted the classical 3(10)-helical binding conformation. This suggests the 3(10)-helical conformation is critical to high affinity PCNA binding, however NMR secondary shift analysis of peptide 7 revealed this secondary structure was not well-defined in solution. Peptide 7 is cell permeable and localised to the cell cytosol of breast cancer cells (MDA-MB-468), revealed by confocal microscopy showing blue fluorescence of the bimane linker. The inherent fluorescence of the bimane moiety present in peptide 7 allowed it to be directly imaged in the cell uptake assay, without attachment of an auxiliary fluorescent tag. This highlights a significant benefit of using a bimane constraint to access conformationally constrained macrocyclic peptides. This study identifies a small peptidomimetic that binds PCNA with higher affinity than previous reported p21 macrocycles, and is cell permeable, providing a significant advance toward development of a PCNA inhibitor for therapeutic applications.
		+
		+	A cell permeable bimane-constrained PCNA-interacting peptide.,Horsfall AJ, Vandborg BA, Kikhtyak Z, Scanlon DB, Tilley WD, Hickey TE, Bruning JB, Abell AD RSC Chem Biol. 2021 Jul 21;2(5):1499-1508. doi: 10.1039/d1cb00113b. eCollection , 2021 Oct 7. PMID:34704055<ref>PMID:34704055</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7m5n" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Proliferating cell nuclear antigen 3D structures\|Proliferating cell nuclear antigen 3D structures]]
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~Z-disk~~]]	+	[[Category: Synthetic construct]]
		+	[[Category: Bruning JB]]
		+	[[Category: Vandborg BA]]

OCA at 06:07, 11 August 2021

OCA — Wed, 11 Aug 2021 06:07:48 GMT

←Older revision		Revision as of 06:07, 11 August 2021
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 7m5n ~~is ON HOLD until Paper Publication~~	+	====
-		+	<StructureSection load='7m5n' size='340' side='right'caption='[[7m5n]]' scene=''>
-	~~Authors~~: ~~Vandborg, B~~.A.~~, Bruning, J~~.B.	+	== 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~~: ~~PCNA bound to peptide mimetic with linker~~	+	</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=7m5n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7m5n OCA], [https://pdbe.org/7m5n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7m5n RCSB], [https://www.ebi.ac.uk/pdbsum/7m5n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7m5n ProSAT]</span></td></tr>
-	[[~~Category~~: ~~Unreleased Structures~~]]	+	</table>
-	[[~~Category~~: ~~Bruning~~, J.B]]	+	__TOC__
-	[[Category: ~~Vandborg, B.A~~]]	+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Z-disk]]

OCA at 13:27, 2 June 2021

OCA — Wed, 02 Jun 2021 13:27:11 GMT

←Older revision		Revision as of 13:27, 2 June 2021
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7m5n is ON HOLD	+	The entry 7m5n is ON HOLD until Paper Publication

	Authors: Vandborg, B.A., Bruning, J.B.		Authors: Vandborg, B.A., Bruning, J.B.

OCA: Protected "7m5n" [edit=sysop:move=sysop]

OCA — Wed, 31 Mar 2021 09:24:33 GMT

Protected "7m5n" [edit=sysop:move=sysop]

←Older revision

Revision as of 09:24, 31 March 2021

OCA: New page: '''Unreleased structure''' The entry 7m5n is ON HOLD Authors: Vandborg, B.A., Bruning, J.B. Description: PCNA bound to peptide mimetic with linker Category: Unreleased Structures [...

OCA — Wed, 31 Mar 2021 09:24:32 GMT

New page: '''Unreleased structure''' The entry 7m5n is ON HOLD Authors: Vandborg, B.A., Bruning, J.B. Description: PCNA bound to peptide mimetic with linker Category: Unreleased Structures [...

New page

'''Unreleased structure'''

The entry 7m5n is ON HOLD

Authors: Vandborg, B.A., Bruning, J.B.

Description: PCNA bound to peptide mimetic with linker
[[Category: Unreleased Structures]]
[[Category: Bruning, J.B]]
[[Category: Vandborg, B.A]]

7m5n - Revision history

OCA at 16:05, 18 October 2023

OCA at 06:07, 11 August 2021

OCA at 13:27, 2 June 2021

OCA: Protected "7m5n" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 7m5n is ON HOLD Authors: Vandborg, B.A., Bruning, J.B. Description: PCNA bound to peptide mimetic with linker Category: Unreleased Structures [...