OCA at 16:20, 18 October 2023

OCA — Wed, 18 Oct 2023 16:20:51 GMT

←Older revision		Revision as of 16:20, 18 October 2023
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-	====	+	==PLK-1 polo-box domain in complex with a high affinity macrocycle synthesized using a novel glutamic acid analog==
-	<StructureSection load='7mx1' size='340' side='right'caption='[[7mx1]]' scene=''>	+	<StructureSection load='7mx1' size='340' side='right'caption='[[7mx1]], [[Resolution\|resolution]] 1.64Å' 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'>[[7mx1]] is a 4 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=7MX1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MX1 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=7mx1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mx1 OCA], [https://pdbe.org/7mx1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mx1 RCSB], [https://www.ebi.ac.uk/pdbsum/7mx1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mx1 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]] 1.64Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene>, <scene name='pdbligand=ZOY:N-[(4S)-4,5-diamino-5-oxopentyl]-10-phenyldecanamide'>ZOY</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=7mx1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mx1 OCA], [https://pdbe.org/7mx1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mx1 RCSB], [https://www.ebi.ac.uk/pdbsum/7mx1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mx1 ProSAT]</span></td></tr>
	</table>		</table>
		+	== Disease ==
		+	[https://www.uniprot.org/uniprot/PLK1_HUMAN PLK1_HUMAN] Note=Defects in PLK1 are associated with some cancers, such as gastric, thyroid or B-cell lymphomas. Expression is cancer increased in tumor tissues with a poor prognosis, suggesting a role in malignant transformations and carcinogenesis.
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/PLK1_HUMAN PLK1_HUMAN] Serine/threonine-protein kinase that performs several important functions throughout M phase of the cell cycle, including the regulation of centrosome maturation and spindle assembly, the removal of cohesins from chromosome arms, the inactivation of anaphase-promoting complex/cyclosome (APC/C) inhibitors, and the regulation of mitotic exit and cytokinesis. Polo-like kinase proteins acts by binding and phosphorylating proteins are that already phosphorylated on a specific motif recognized by the POLO box domains. Phosphorylates BORA, BUB1B/BUBR1, CCNB1, CDC25C, CEP55, ECT2, ERCC6L, FBXO5/EMI1, FOXM1, KIF20A/MKLP2, MLF1IP, NEDD1, NINL, NPM1, NUDC, PKMYT1/MYT1, PLK1S1/KIZ, PPP1R12A/MYPT1, PRC1, RACGAP1/CYK4, SGOL1, STAG2/SA2, TEX14, TOPORS, p73/TP73, TPT1 and WEE1. Plays a key role in centrosome functions and the assembly of bipolar spindles by phosphorylating PLK1S1/KIZ, NEDD1 and NINL. NEDD1 phosphorylation promotes subsequent targeting of the gamma-tubulin ring complex (gTuRC) to the centrosome, an important step for spindle formation. Phosphorylation of NINL component of the centrosome leads to NINL dissociation from other centrosomal proteins. Involved in mitosis exit and cytokinesis by phosphorylating CEP55, ECT2, KIF20A/MKLP2, MLF1IP, PRC1 and RACGAP1. Recruited at the central spindle by phosphorylating and docking PRC1 and KIF20A/MKLP2; creates its own docking sites on PRC1 and KIF20A/MKLP2 by mediating phosphorylation of sites subsequently recognized by the POLO box domains. Phosphorylates RACGAP1, thereby creating a docking site for the Rho GTP exchange factor ECT2 that is essential for the cleavage furrow formation. Promotes the central spindle recruitment of ECT2. Plays a central role in G2/M transition of mitotic cell cycle by phosphorylating CCNB1, CDC25C, FOXM1, MLF1IP, PKMYT1/MYT1, PPP1R12A/MYPT1 and WEE1. Part of a regulatory circuit that promotes the activation of CDK1 by phosphorylating the positive regulator CDC25C and inhibiting the negative regulators WEE1 and PKMYT1/MYT1. Also acts by mediating phosphorylation of cyclin-B1 (CCNB1) on centrosomes in prophase. Phosphorylates FOXM1, a key mitotic transcription regulator, leading to enhance FOXM1 transcriptional activity. Involved in kinetochore functions and sister chromatid cohesion by phosphorylating BUB1B/BUBR1, FBXO5/EMI1 and STAG2/SA2. PLK1 is high on non-attached kinetochores suggesting a role of PLK1 in kinetochore attachment or in spindle assembly checkpoint (SAC) regulation. Required for kinetochore localization of BUB1B. Regulates the dissociation of cohesin from chromosomes by phosphorylating cohesin subunits such as STAG2/SA2. Phosphorylates SGOL1: required for spindle pole localization of isoform 3 of SGOL1 and plays a role in regulating its centriole cohesion function. Mediates phosphorylation of FBXO5/EMI1, a negative regulator of the APC/C complex during prophase, leading to FBXO5/EMI1 ubiquitination and degradation by the proteasome. Acts as a negative regulator of p53 family members: phosphorylates TOPORS, leading to inhibit the sumoylation of p53/TP53 and simultaneously enhance the ubiquitination and subsequent degradation of p53/TP53. Phosphorylates the transactivation domain of the transcription factor p73/TP73, leading to inhibit p73/TP73-mediated transcriptional activation and pro-apoptotic functions. Phosphorylates BORA, and thereby promotes the degradation of BORA. Contributes to the regulation of AURKA function. Also required for recovery after DNA damage checkpoint and entry into mitosis.<ref>PMID:8991084</ref> <ref>PMID:11202906</ref> <ref>PMID:12207013</ref> <ref>PMID:12447691</ref> <ref>PMID:12852856</ref> <ref>PMID:12738781</ref> <ref>PMID:12939256</ref> <ref>PMID:12524548</ref> <ref>PMID:14734534</ref> <ref>PMID:15469984</ref> <ref>PMID:15070733</ref> <ref>PMID:15148369</ref> <ref>PMID:16198290</ref> <ref>PMID:16980960</ref> <ref>PMID:16247472</ref> <ref>PMID:17081991</ref> <ref>PMID:17617734</ref> <ref>PMID:17376779</ref> <ref>PMID:17351640</ref> <ref>PMID:18418051</ref> <ref>PMID:18521620</ref> <ref>PMID:18331714</ref> <ref>PMID:18477460</ref> <ref>PMID:18174154</ref> <ref>PMID:19160488</ref> <ref>PMID:18615013</ref> <ref>PMID:19473992</ref> <ref>PMID:19509060</ref> <ref>PMID:19351716</ref> <ref>PMID:19468300</ref> <ref>PMID:19468302</ref> <ref>PMID:14532005</ref> <ref>PMID:19597481</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Targeting protein - protein interactions (PPIs) has emerged as an important area of discovery for anticancer therapeutic development. In the case of phospho-dependent PPIs, such as the polo-like kinase 1 (Plk1) polo-box domain (PBD), a phosphorylated protein residue can provide high-affinity recognition and binding to target protein hot spots. Developing antagonists of the Plk1 PBD can be particularly challenging if one relies solely on interactions within and proximal to the phospho-binding pocket. Fortunately, the affinity of phospho-dependent PPI antagonists can be significantly enhanced by taking advantage of interactions in both the phospho-binding site and hidden "cryptic" pockets that may be revealed on ligand binding. In our current paper, we describe the design and synthesis of macrocyclic peptide mimetics directed against the Plk1 PBD, which are characterized by a new glutamic acid analog that simultaneously serves as a ring-closing junction that provides accesses to a cryptic binding pocket, while at the same time achieving proper orientation of a phosphothreonine (pT) residue for optimal interaction in the signature phospho-binding pocket. Macrocycles prepared with this new amino acid analog introduce additional hydrogen-bonding interactions not found in the open-chain linear parent peptide. It is noteworthy that this new glutamic acid-based amino acid analog represents the first example of extremely high affinity ligands where access to the cryptic pocket from the pT-2 position is made possible with a residue that is not based on histidine. The concepts employed in the design and synthesis of these new macrocyclic peptide mimetics should be useful for further studies directed against the Plk1 PBD and potentially for ligands directed against other PPI targets.
		+
		+	Design and synthesis of a new orthogonally protected glutamic acid analog and its use in the preparation of high affinity polo-like kinase 1 polo-box domain - binding peptide macrocycles.,Hymel D, Tsuji K, Grant RA, Chingle RM, Kunciw DL, Yaffe MB, Burke TR Jr Org Biomol Chem. 2021 Sep 22;19(36):7843-7854. doi: 10.1039/d1ob01120k. PMID:34346472<ref>PMID:34346472</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7mx1" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Serine/threonine protein kinase 3D structures\|Serine/threonine protein kinase 3D structures]]
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~Z-disk~~]]	+	[[Category: Burke TR]]
		+	[[Category: Grant RA]]
		+	[[Category: Hymel D]]
		+	[[Category: Yaffe MB]]

OCA at 10:44, 30 March 2022

OCA — Wed, 30 Mar 2022 10:44:59 GMT

←Older revision		Revision as of 10:44, 30 March 2022
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-	'''Unreleased structure'''

-	~~The entry~~ 7mx1 ~~is ON HOLD until Paper Publication~~	+	====
-		+	<StructureSection load='7mx1' size='340' side='right'caption='[[7mx1]]' scene=''>
-	~~Authors~~: ~~Grant, R~~.A.~~, Hymel, D~~.~~, Yaffe, M~~.B.~~, Burke, T~~.R.	+	== 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~~: ~~PLK-1 polo-box domain in complex with a high affinity macrocycle synthesized using a novel glutamic acid analog~~	+	</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=7mx1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mx1 OCA], [https://pdbe.org/7mx1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mx1 RCSB], [https://www.ebi.ac.uk/pdbsum/7mx1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mx1 ProSAT]</span></td></tr>
-	[~~[Category~~: ~~Unreleased Structures~~]]	+	</table>
-	[~~[Category~~: ~~Burke~~, T.R]]	+	__TOC__
-	[~~[Category~~: ~~Yaffe~~, M.B]]	+	</StructureSection>
-	[[Category: ~~Hymel, D~~]]	+	[[Category: Large Structures]]
-	[[Category: ~~Grant, R.A~~]]	+	[[Category: Z-disk]]

OCA at 06:11, 25 June 2021

OCA — Fri, 25 Jun 2021 06:11:55 GMT

←Older revision		Revision as of 06:11, 25 June 2021
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7mx1 is ON HOLD	+	The entry 7mx1 is ON HOLD until Paper Publication

	Authors: Grant, R.A., Hymel, D., Yaffe, M.B., Burke, T.R.		Authors: Grant, R.A., Hymel, D., Yaffe, M.B., Burke, T.R.
Line 7:		Line 7:
	Description: PLK-1 polo-box domain in complex with a high affinity macrocycle synthesized using a novel glutamic acid analog		Description: PLK-1 polo-box domain in complex with a high affinity macrocycle synthesized using a novel glutamic acid analog
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
-	[[Category: Yaffe, M.B]]
	[[Category: Burke, T.R]]		[[Category: Burke, T.R]]
		+	[[Category: Yaffe, M.B]]
	[[Category: Hymel, D]]		[[Category: Hymel, D]]
	[[Category: Grant, R.A]]		[[Category: Grant, R.A]]

OCA: Protected "7mx1" [edit=sysop:move=sysop]

OCA — Wed, 26 May 2021 08:01:28 GMT

Protected "7mx1" [edit=sysop:move=sysop]

←Older revision

Revision as of 08:01, 26 May 2021

OCA: New page: '''Unreleased structure''' The entry 7mx1 is ON HOLD Authors: Grant, R.A., Hymel, D., Yaffe, M.B., Burke, T.R. Description: PLK-1 polo-box domain in complex with a high affinity macroc...

OCA — Wed, 26 May 2021 08:01:27 GMT

New page: '''Unreleased structure''' The entry 7mx1 is ON HOLD Authors: Grant, R.A., Hymel, D., Yaffe, M.B., Burke, T.R. Description: PLK-1 polo-box domain in complex with a high affinity macroc...

New page

'''Unreleased structure'''

The entry 7mx1 is ON HOLD

Authors: Grant, R.A., Hymel, D., Yaffe, M.B., Burke, T.R.

Description: PLK-1 polo-box domain in complex with a high affinity macrocycle synthesized using a novel glutamic acid analog
[[Category: Unreleased Structures]]
[[Category: Yaffe, M.B]]
[[Category: Burke, T.R]]
[[Category: Hymel, D]]
[[Category: Grant, R.A]]

7mx1 - Revision history

OCA at 16:20, 18 October 2023

OCA at 10:44, 30 March 2022

OCA at 06:11, 25 June 2021

OCA: Protected "7mx1" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 7mx1 is ON HOLD Authors: Grant, R.A., Hymel, D., Yaffe, M.B., Burke, T.R. Description: PLK-1 polo-box domain in complex with a high affinity macroc...