6g9k - Revision history

OCA at 06:32, 18 October 2018

OCA — Thu, 18 Oct 2018 06:32:50 GMT

←Older revision		Revision as of 06:32, 18 October 2018
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	</div>		</div>
	<div class="pdbe-citations 6g9k" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 6g9k" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Mitogen-activated protein kinase\|Mitogen-activated protein kinase]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 08:17, 14 June 2018

OCA — Thu, 14 Jun 2018 08:17:50 GMT

←Older revision		Revision as of 08:17, 14 June 2018
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	<StructureSection load='6g9k' size='340' side='right' caption='[[6g9k]], [[Resolution\|resolution]] 1.94Å' scene=''>		<StructureSection load='6g9k' size='340' side='right' caption='[[6g9k]], [[Resolution\|resolution]] 1.94Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6g9k]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6G9K OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6G9K FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6g9k]] 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=6G9K OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6G9K FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ESK:2-[5-[5-chloranyl-2-(oxan-4-ylamino)pyrimidin-4-yl]-3-oxidanylidene-1~{H}-isoindol-2-yl]-~{N}-[(1~{S})-2-oxidanyl-1-phenyl-ethyl]ethanamide'>ESK</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ESK:2-[5-[5-chloranyl-2-(oxan-4-ylamino)pyrimidin-4-yl]-3-oxidanylidene-1~{H}-isoindol-2-yl]-~{N}-[(1~{S})-2-oxidanyl-1-phenyl-ethyl]ethanamide'>ESK</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</scene></td></tr>		<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">MAPK1, ERK2, PRKM1, PRKM2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase Mitogen-activated protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.24 2.7.11.24] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase Mitogen-activated protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.24 2.7.11.24] </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=6g9k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6g9k OCA], [http://pdbe.org/6g9k PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6g9k RCSB], [http://www.ebi.ac.uk/pdbsum/6g9k PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6g9k ProSAT]</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=6g9k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6g9k OCA], [http://pdbe.org/6g9k PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6g9k RCSB], [http://www.ebi.ac.uk/pdbsum/6g9k PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6g9k ProSAT]</span></td></tr>
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	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Mitogen-activated protein kinase]]		[[Category: Mitogen-activated protein kinase]]
	[[Category: Reilly, M O]]		[[Category: Reilly, M O]]
	[[Category: Erk2 kinase inhibitor]]		[[Category: Erk2 kinase inhibitor]]
	[[Category: Signaling protein]]		[[Category: Signaling protein]]

OCA at 05:40, 30 May 2018

OCA — Wed, 30 May 2018 05:40:30 GMT

←Older revision		Revision as of 05:40, 30 May 2018
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-	'''Unreleased structure'''

-	~~The entry~~ 6g9k is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Fragment-based discovery of a highly potent, orally bioavailable inhibitor which modulates the phosphorylation and catalytic activity of ERK1/2==
		+	<StructureSection load='6g9k' size='340' side='right' caption='[[6g9k]], [[Resolution\|resolution]] 1.94Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6g9k]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6G9K OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6G9K FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ESK:2-[5-[5-chloranyl-2-(oxan-4-ylamino)pyrimidin-4-yl]-3-oxidanylidene-1~{H}-isoindol-2-yl]-~{N}-[(1~{S})-2-oxidanyl-1-phenyl-ethyl]ethanamide'>ESK</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
		+	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</scene></td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase Mitogen-activated protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.24 2.7.11.24] </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=6g9k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6g9k OCA], [http://pdbe.org/6g9k PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6g9k RCSB], [http://www.ebi.ac.uk/pdbsum/6g9k PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6g9k ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/MK01_HUMAN MK01_HUMAN]] Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important role in the MAPK/ERK cascade. They participate also in a signaling cascade initiated by activated KIT and KITLG/SCF. Depending on the cellular context, the MAPK/ERK cascade mediates diverse biological functions such as cell growth, adhesion, survival and differentiation through the regulation of transcription, translation, cytoskeletal rearrangements. The MAPK/ERK cascade plays also a role in initiation and regulation of meiosis, mitosis, and postmitotic functions in differentiated cells by phosphorylating a number of transcription factors. About 160 substrates have already been discovered for ERKs. Many of these substrates are localized in the nucleus, and seem to participate in the regulation of transcription upon stimulation. However, other substrates are found in the cytosol as well as in other cellular organelles, and those are responsible for processes such as translation, mitosis and apoptosis. Moreover, the MAPK/ERK cascade is also involved in the regulation of the endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC); as well as in the fragmentation of the Golgi apparatus during mitosis. The substrates include transcription factors (such as ATF2, BCL6, ELK1, ERF, FOS, HSF4 or SPZ1), cytoskeletal elements (such as CANX, CTTN, GJA1, MAP2, MAPT, PXN, SORBS3 or STMN1), regulators of apoptosis (such as BAD, BTG2, CASP9, DAPK1, IER3, MCL1 or PPARG), regulators of translation (such as EIF4EBP1) and a variety of other signaling-related molecules (like ARHGEF2, DCC, FRS2 or GRB10). Protein kinases (such as RAF1, RPS6KA1/RSK1, RPS6KA3/RSK2, RPS6KA2/RSK3, RPS6KA6/RSK4, SYK, MKNK1/MNK1, MKNK2/MNK2, RPS6KA5/MSK1, RPS6KA4/MSK2, MAPKAPK3 or MAPKAPK5) and phosphatases (such as DUSP1, DUSP4, DUSP6 or DUSP16) are other substrates which enable the propagation the MAPK/ERK signal to additional cytosolic and nuclear targets, thereby extending the specificity of the cascade. May play a role in the spindle assembly checkpoint.<ref>PMID:7588608</ref> <ref>PMID:8622688</ref> <ref>PMID:9480836</ref> <ref>PMID:9687510</ref> <ref>PMID:9649500</ref> <ref>PMID:9596579</ref> <ref>PMID:10637505</ref> <ref>PMID:10617468</ref> <ref>PMID:11154262</ref> <ref>PMID:12110590</ref> <ref>PMID:12356731</ref> <ref>PMID:12974390</ref> <ref>PMID:12794087</ref> <ref>PMID:12792650</ref> <ref>PMID:15184391</ref> <ref>PMID:15241487</ref> <ref>PMID:15952796</ref> <ref>PMID:15616583</ref> <ref>PMID:15788397</ref> <ref>PMID:15664191</ref> <ref>PMID:16581800</ref> <ref>PMID:19879846</ref> <ref>PMID:19265199</ref> Acts as a transcriptional repressor. Binds to a [GC]AAA[GC] consensus sequence. Repress the expression of interferon gamma-induced genes. Seems to bind to the promoter of CCL5, DMP1, IFIH1, IFITM1, IRF7, IRF9, LAMP3, OAS1, OAS2, OAS3 and STAT1. Transcriptional activity is independent of kinase activity.<ref>PMID:7588608</ref> <ref>PMID:8622688</ref> <ref>PMID:9480836</ref> <ref>PMID:9687510</ref> <ref>PMID:9649500</ref> <ref>PMID:9596579</ref> <ref>PMID:10637505</ref> <ref>PMID:10617468</ref> <ref>PMID:11154262</ref> <ref>PMID:12110590</ref> <ref>PMID:12356731</ref> <ref>PMID:12974390</ref> <ref>PMID:12794087</ref> <ref>PMID:12792650</ref> <ref>PMID:15184391</ref> <ref>PMID:15241487</ref> <ref>PMID:15952796</ref> <ref>PMID:15616583</ref> <ref>PMID:15788397</ref> <ref>PMID:15664191</ref> <ref>PMID:16581800</ref> <ref>PMID:19879846</ref> <ref>PMID:19265199</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signalling through ERK1/2. Here we describe the fragment based generation of ERK1/2 inhibitors which block catalytic phosphorylation of downstream substrates such as RSK but also modulate phosphorylation of ERK1/2 by MEK without directly inhibiting MEK. X-ray crystallographic and biophysical fragment screening followed by structure-guided optimization and growth from the hinge into a pocket proximal to the C-alpha helix afforded highly potent ERK1/2 inhibitors with excellent kinome selectivity. In BRAF mutant cells the lead compound suppresses pRSK and pERK levels and inhibits proliferation at low nanomolar concentrations. The lead exhibits tumor regression upon oral dosing in BRAF mutant xenograft models, providing a promising basis for further optimization towards clinical pERK1/2 modulating ERK1/2 inhibitors.

-	~~Authors:~~ O'Reilly, M.	+	Fragment-based discovery of a potent, orally bioavailable inhibitor which modulates the phosphorylation and catalytic activity of ERK1/2.,Heightman TD, Berdini V, Braithwaite H, Buck IM, Cassidy M, Castro J, Courtin A, Day JEH, East C, Fazal L, Graham B, Griffiths-Jones CM, Lyons JF, Martins V, Muench S, Munck JM, Norton D, O'Reilly M, Palmer N, Pathuri P, Reader M, Rees DC, Rich SJ, Richardson C, Saini H, Thompson NT, Wallis NG, Walton H, Wilsher NE, Woolford AJ, Cooke M, Cousin D, Onions S, Shannon J, Watts J, Murray CW J Med Chem. 2018 May 18. doi: 10.1021/acs.jmedchem.8b00421. PMID:29775310<ref>PMID:29775310</ref>

-	~~Description: Fragment-based discovery of a highly potent~~, ~~orally bioavailable inhibitor which modulates~~ the ~~phosphorylation and catalytic activity~~ of ~~ERK1~~/2	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
-	[[Category: O'Reilly, M]]	+	<div class="pdbe-citations 6g9k" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Mitogen-activated protein kinase]]
		+	[[Category: Reilly, M O]]
		+	[[Category: Erk2 kinase inhibitor]]
		+	[[Category: Signaling protein]]

OCA at 06:51, 2 May 2018

OCA — Wed, 02 May 2018 06:51:35 GMT

←Older revision		Revision as of 06:51, 2 May 2018
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6g9k is ON HOLD	+	The entry 6g9k is ON HOLD until Paper Publication

	Authors: O'Reilly, M.		Authors: O'Reilly, M.

OCA: Protected "6g9k" [edit=sysop:move=sysop]

OCA — Wed, 18 Apr 2018 04:30:59 GMT

Protected "6g9k" [edit=sysop:move=sysop]

←Older revision

Revision as of 04:30, 18 April 2018

OCA: New page: '''Unreleased structure''' The entry 6g9k is ON HOLD Authors: O'Reilly, M. Description: Fragment-based discovery of a highly potent, orally bioavailable inhibitor which modulates the p...

OCA — Wed, 18 Apr 2018 04:30:58 GMT

New page: '''Unreleased structure''' The entry 6g9k is ON HOLD Authors: O'Reilly, M. Description: Fragment-based discovery of a highly potent, orally bioavailable inhibitor which modulates the p...

New page

'''Unreleased structure'''

The entry 6g9k is ON HOLD

Authors: O'Reilly, M.

Description: Fragment-based discovery of a highly potent, orally bioavailable inhibitor which modulates the phosphorylation and catalytic activity of ERK1/2
[[Category: Unreleased Structures]]
[[Category: O'Reilly, M]]