5hes - Revision history

OCA at 07:33, 9 August 2023

OCA — Wed, 09 Aug 2023 07:33:37 GMT

←Older revision		Revision as of 07:33, 9 August 2023
Line 3:		Line 3:
	<StructureSection load='5hes' size='340' side='right'caption='[[5hes]], [[Resolution\|resolution]] 2.14Å' scene=''>		<StructureSection load='5hes' size='340' side='right'caption='[[5hes]], [[Resolution\|resolution]] 2.14Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5hes]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HES OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=5HES FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5hes]] is a 2 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=5HES OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5HES FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=032:N-(3-{[5-(4-CHLOROPHENYL)-1H-PYRROLO[2,3-B]PYRIDIN-3-YL]CARBONYL}-2,4-DIFLUOROPHENYL)PROPANE-1-SULFONAMIDE'>032</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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]] 2.14Å</td></tr>
-	~~<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat">~~<scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene~~></td></tr>~~	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=032:N-(3-{[5-(4-CHLOROPHENYL)-1H-PYRROLO[2,3-B]PYRIDIN-3-YL]CARBONYL}-2,4-DIFLUOROPHENYL)PROPANE-1-SULFONAMIDE'>032</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</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_kinase_kinase Mitogen-activated protein kinase kinase kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.25 2.7.11.25] </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=5hes FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hes OCA], [https://pdbe.org/5hes PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5hes RCSB], [https://www.ebi.ac.uk/pdbsum/5hes PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5hes 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=5hes FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hes OCA], [~~http~~://pdbe.org/5hes PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5hes RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5hes PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5hes ProSAT]</span></td></tr>	+
	</table>		</table>
		+	== Disease ==
		+	[https://www.uniprot.org/uniprot/M3K20_HUMAN M3K20_HUMAN] Split-foot malformation-mesoaxial polydactyly syndrome;Congenital fiber-type disproportion myopathy. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry.
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/~~MLTK_HUMAN MLTK_HUMAN]~~] Stress-activated component of a protein kinase signal transduction cascade. ~~Regulates~~ the JNK and p38 pathways. ~~Pro-apoptotic~~. ~~Role~~ in regulation of S and G2 cell cycle checkpoint by ~~direct~~ phosphorylation of CHEK2. ~~Isoform 1~~, ~~but not isoform 2~~, ~~causes cell shrinkage and disruption~~ of ~~actin~~ stress ~~fibers~~. ~~Isoform 1 may have role in neoplastic~~ cell ~~transformation~~ and ~~cancer development~~. ~~Isoform 1~~, ~~but not isoform~~ 2, phosphorylates histone H3 at 'Ser-28'.<ref>PMID:~~10924358~~</ref> <ref>PMID:~~11042189~~</ref> <ref>PMID:~~11836244~~</ref> <ref>PMID:~~15172994~~</ref> <ref>PMID:~~15342622~~</ref> <ref>PMID:~~15684425~~</ref>	+	[https://www.uniprot.org/uniprot/M3K20_HUMAN M3K20_HUMAN] Stress-activated component of a protein kinase signal transduction cascade that promotes programmed cell death in response to various stress, such as ribosomal stress, osmotic shock and ionizing radiation (PubMed:10924358, PubMed:11836244, PubMed:12220515, PubMed:14521931, PubMed:15350844, PubMed:15737997, PubMed:18331592, PubMed:20559024, PubMed:32610081, PubMed:32289254, PubMed:35857590, PubMed:26999302). Acts by catalyzing phosphorylation of MAP kinase kinases, leading to activation of the JNK (MAPK8/JNK1, MAPK9/JNK2 and/or MAPK10/JNK3) and MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14) pathways (PubMed:11042189, PubMed:11836244, PubMed:12220515, PubMed:14521931, PubMed:15172994, PubMed:15737997, PubMed:32610081, PubMed:32289254, PubMed:35857590). Activates JNK through phosphorylation of MAP2K4/MKK4 and MAP2K7/MKK7, and MAP kinase p38 gamma (MAPK12) via phosphorylation of MAP2K3/MKK3 and MAP2K6/MKK6 (PubMed:11836244, PubMed:12220515). Involved in stress associated with adrenergic stimulation: contributes to cardiac decompensation during periods of acute cardiac stress (PubMed:15350844, PubMed:21224381, PubMed:27859413). May be involved in regulation of S and G2 cell cycle checkpoint by mediating phosphorylation of CHEK2 (PubMed:15342622).<ref>PMID:10924358</ref> <ref>PMID:11042189</ref> <ref>PMID:11836244</ref> <ref>PMID:12220515</ref> <ref>PMID:14521931</ref> <ref>PMID:15172994</ref> <ref>PMID:15342622</ref> <ref>PMID:15350844</ref> <ref>PMID:15737997</ref> <ref>PMID:18331592</ref> <ref>PMID:20559024</ref> <ref>PMID:21224381</ref> <ref>PMID:26999302</ref> <ref>PMID:27859413</ref> <ref>PMID:32289254</ref> <ref>PMID:32610081</ref> <ref>PMID:35857590</ref> Key component of the stress-activated protein kinase signaling cascade in response to ribotoxic stress or UV-B irradiation (PubMed:32610081, PubMed:32289254, PubMed:35857590). Acts as the proximal sensor of ribosome collisions during the ribotoxic stress response (RSR): directly binds to the ribosome by inserting its flexible C-terminus into the ribosomal intersubunit space, thereby acting as a sentinel for colliding ribosomes (PubMed:32610081, PubMed:32289254). Upon ribosome collisions, activates either the stress-activated protein kinase signal transduction cascade or the integrated stress response (ISR), leading to programmed cell death or cell survival, respectively (PubMed:32610081). Dangerous levels of ribosome collisions trigger the autophosphorylation and activation of MAP3K20, which dissociates from colliding ribosomes and phosphorylates MAP kinase kinases, leading to activation of the JNK and MAP kinase p38 pathways that promote programmed cell death (PubMed:32610081, PubMed:32289254). Less dangerous levels of ribosome collisions trigger the integrated stress response (ISR): MAP3K20 activates EIF2AK4/GCN2 independently of its protein-kinase activity, promoting EIF2AK4/GCN2-mediated phosphorylation of EIF2S1/eIF-2-alpha (PubMed:32610081). Also part of the stress-activated protein kinase signaling cascade triggering the NLRP1 inflammasome in response to UV-B irradiation: ribosome collisions activate MAP3K20, which directly phosphorylates NLRP1, leading to activation of the NLRP1 inflammasome and subsequent pyroptosis (PubMed:35857590). NLRP1 is also phosphorylated by MAP kinase p38 downstream of MAP3K20 (PubMed:35857590). Also acts as a histone kinase by phosphorylating histone H3 at 'Ser-28' (H3S28ph) (PubMed:15684425).<ref>PMID:15684425</ref> <ref>PMID:32289254</ref> <ref>PMID:32610081</ref> <ref>PMID:35857590</ref> Isoform that lacks the C-terminal region that mediates ribosome-binding: does not act as a sensor of ribosome collisions in response to ribotoxic stress (PubMed:32610081, PubMed:32289254, PubMed:35857590). May act as an antagonist of isoform ZAKalpha: interacts with isoform ZAKalpha, leading to decrease the expression of isoform ZAKalpha (PubMed:27859413).<ref>PMID:27859413</ref> <ref>PMID:32289254</ref> <ref>PMID:32610081</ref> <ref>PMID:35857590</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 24:		Line 25:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~Mitogen-activated protein kinase kinase kinase~~]]	+	[[Category: Abdul Azeez KR]]
-	[[Category: Arrowsmith~~, C H]]~~	+	[[Category: Arrowsmith CH]]
-	~~[[Category: Azeez, K R.Abdul~~]]	+	[[Category: Bountra C]]
-	[[Category: Bountra, C]]	+	[[Category: Burgess-Brown N]]
-	[[Category: Burgess-Brown, N]]	+	[[Category: Chaikuad A]]
-	[[Category: Chaikuad, A]]	+	[[Category: Edwards AM]]
-	~~[[Category: Delft, F von~~]]	+	[[Category: Elkins JM]]
-	[[Category: Edwards~~, A M~~]]	+	[[Category: Knapp S]]
-	[[Category: Elkins~~, J M~~]]	+	[[Category: Mathea S]]
-	[[Category: Knapp, S]]	+	[[Category: Salah E]]
-	[[Category: Mathea, S]]	+	[[Category: Shrestha B]]
-	[[Category: Salah, E]]	+	[[Category: Shrestha L]]
-	[[Category: Shrestha, B]]	+	[[Category: Sorrell FJ]]
-	[[Category: Shrestha, L]]	+	[[Category: Szklarz M]]
-	[[Category: Sorrell~~, F J~~]]	+	[[Category: Tallant C]]
-	[[Category: Szklarz, M]]	+	[[Category: Von Delft F]]
-	[[Category: Tallant, C]]	+
-	[[Category: ~~Complex]]~~	+
-	~~[[Category: Kinase]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 07:02, 20 May 2020

OCA — Wed, 20 May 2020 07:02:54 GMT

←Older revision		Revision as of 07:02, 20 May 2020
Line 1:		Line 1:

	==Human leucine zipper- and sterile alpha motif-containing kinase (ZAK, MLT, HCCS-4, MRK, AZK, MLTK) in complex with vemurafenib==		==Human leucine zipper- and sterile alpha motif-containing kinase (ZAK, MLT, HCCS-4, MRK, AZK, MLTK) in complex with vemurafenib==
-	<StructureSection load='5hes' size='340' side='right' caption='[[5hes]], [[Resolution\|resolution]] 2.14Å' scene=''>	+	<StructureSection load='5hes' size='340' side='right'caption='[[5hes]], [[Resolution\|resolution]] 2.14Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5hes]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HES OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5HES FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5hes]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HES OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5HES FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=032:N-(3-{[5-(4-CHLOROPHENYL)-1H-PYRROLO[2,3-B]PYRIDIN-3-YL]CARBONYL}-2,4-DIFLUOROPHENYL)PROPANE-1-SULFONAMIDE'>032</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=032:N-(3-{[5-(4-CHLOROPHENYL)-1H-PYRROLO[2,3-B]PYRIDIN-3-YL]CARBONYL}-2,4-DIFLUOROPHENYL)PROPANE-1-SULFONAMIDE'>032</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>		<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</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_kinase_kinase Mitogen-activated protein kinase kinase kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.25 2.7.11.25] </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_kinase_kinase Mitogen-activated protein kinase kinase kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.25 2.7.11.25] </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=5hes FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hes OCA], [http://pdbe.org/5hes PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5hes RCSB], [http://www.ebi.ac.uk/pdbsum/5hes PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5hes 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=5hes FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hes OCA], [http://pdbe.org/5hes PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5hes RCSB], [http://www.ebi.ac.uk/pdbsum/5hes PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5hes ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 24:		Line 24:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Large Structures]]
	[[Category: Mitogen-activated protein kinase kinase kinase]]		[[Category: Mitogen-activated protein kinase kinase kinase]]
	[[Category: Arrowsmith, C H]]		[[Category: Arrowsmith, C H]]

OCA at 18:30, 12 July 2016

OCA — Tue, 12 Jul 2016 18:30:52 GMT

←Older revision		Revision as of 18:30, 12 July 2016
Line 7:		Line 7:
	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>		<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</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_kinase_kinase Mitogen-activated protein kinase kinase kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.25 2.7.11.25] </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_kinase_kinase Mitogen-activated protein kinase kinase kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.25 2.7.11.25] </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=5hes FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hes OCA], [http://pdbe.org/5hes PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5hes RCSB], [http://www.ebi.ac.uk/pdbsum/5hes PDBsum]</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=5hes FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hes OCA], [http://pdbe.org/5hes PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5hes RCSB], [http://www.ebi.ac.uk/pdbsum/5hes PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5hes ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==

OCA at 19:33, 10 May 2016

OCA — Tue, 10 May 2016 19:33:38 GMT

←Older revision		Revision as of 19:33, 10 May 2016
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 5hes is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Human leucine zipper- and sterile alpha motif-containing kinase (ZAK, MLT, HCCS-4, MRK, AZK, MLTK) in complex with vemurafenib==
		+	<StructureSection load='5hes' size='340' side='right' caption='[[5hes]], [[Resolution\|resolution]] 2.14Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5hes]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HES OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5HES FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=032:N-(3-{[5-(4-CHLOROPHENYL)-1H-PYRROLO[2,3-B]PYRIDIN-3-YL]CARBONYL}-2,4-DIFLUOROPHENYL)PROPANE-1-SULFONAMIDE'>032</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
		+	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</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_kinase_kinase Mitogen-activated protein kinase kinase kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.25 2.7.11.25] </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=5hes FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hes OCA], [http://pdbe.org/5hes PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5hes RCSB], [http://www.ebi.ac.uk/pdbsum/5hes PDBsum]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/MLTK_HUMAN MLTK_HUMAN]] Stress-activated component of a protein kinase signal transduction cascade. Regulates the JNK and p38 pathways. Pro-apoptotic. Role in regulation of S and G2 cell cycle checkpoint by direct phosphorylation of CHEK2. Isoform 1, but not isoform 2, causes cell shrinkage and disruption of actin stress fibers. Isoform 1 may have role in neoplastic cell transformation and cancer development. Isoform 1, but not isoform 2, phosphorylates histone H3 at 'Ser-28'.<ref>PMID:10924358</ref> <ref>PMID:11042189</ref> <ref>PMID:11836244</ref> <ref>PMID:15172994</ref> <ref>PMID:15342622</ref> <ref>PMID:15684425</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The mixed lineage kinase ZAK is a key regulator of the MAPK pathway mediating cell survival and inflammatory response. ZAK is targeted by several clinically approved kinase inhibitors, and inhibition of ZAK has been reported to protect from doxorubicin-induced cardiomyopathy. On the other hand, unintended targeting of ZAK has been linked to severe adverse effects such as the development of cutaneous squamous cell carcinoma. Therefore, both specific inhibitors of ZAK, as well as anticancer drugs lacking off-target activity against ZAK, may provide therapeutic benefit. Here, we report the first crystal structure of ZAK in complex with the B-RAF inhibitor vemurafenib. The cocrystal structure displayed a number of ZAK-specific features including a highly distorted P loop conformation enabling rational inhibitor design. Positional scanning peptide library analysis revealed a unique substrate specificity of the ZAK kinase including unprecedented preferences for histidine residues at positions -1 and +2 relative to the phosphoacceptor site. In addition, we screened a library of clinical kinase inhibitors identifying several inhibitors that potently inhibit ZAK, demonstrating that this kinase is commonly mistargeted by currently used anticancer drugs.

-	~~Authors:~~ Mathea, S~~., Salah, E.~~, Abdul Azeez, ~~K.R.~~, Tallant, C~~., Sorrell~~, F., ~~Elkins~~, J., ~~Shrestha~~, L., ~~Burgess-Brown, N., von Delft, F., Arrowsmith, C.H., Edwards~~, A~~.M.~~, ~~Bountra~~, C., Knapp, S.	+	Structure of the Human Protein Kinase ZAK in Complex with Vemurafenib.,Mathea S, Abdul Azeez KR, Salah E, Tallant C, Wolfreys F, Konietzny R, Fischer R, Lou HJ, Brennan PE, Schnapp G, Pautsch A, Kessler BM, Turk BE, Knapp S ACS Chem Biol. 2016 Mar 31. PMID:26999302<ref>PMID:26999302</ref>

-	~~Description: Human leucine zipper~~-~~and sterile alpha motif~~-~~containing~~ kinase ~~(ZAK, MLT~~, ~~HCCS-4, MRK, AZK, MLTK) in complex with vemurafenib~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
-	[[Category: ~~Elkins~~, J]]	+	<div class="pdbe-citations 5hes" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Mitogen-activated protein kinase kinase kinase]]
		+	[[Category: Arrowsmith, C H]]
		+	[[Category: Azeez, K R.Abdul]]
		+	[[Category: Bountra, C]]
	[[Category: Burgess-Brown, N]]		[[Category: Burgess-Brown, N]]
		+	[[Category: Chaikuad, A]]
		+	[[Category: Delft, F von]]
		+	[[Category: Edwards, A M]]
		+	[[Category: Elkins, J M]]
	[[Category: Knapp, S]]		[[Category: Knapp, S]]
-	[[Category: Abdul Azeez, K.R]]
-	[[Category: Bountra, C]]
	[[Category: Mathea, S]]		[[Category: Mathea, S]]
-	[[Category: ~~Arrowsmith~~, ~~C.H~~]]	+	[[Category: Salah, E]]
		+	[[Category: Shrestha, B]]
	[[Category: Shrestha, L]]		[[Category: Shrestha, L]]
-	[[Category: ~~Von Delft~~, F]]	+	[[Category: Sorrell, F J]]
-	[[Category: ~~Edwards~~, A.M]]	+	[[Category: Szklarz, M]]
	[[Category: Tallant, C]]		[[Category: Tallant, C]]
-	[[Category: ~~Salah, E~~]]	+	[[Category: Complex]]
-	[[Category: ~~Sorrell, F~~]]	+	[[Category: Kinase]]
		+	[[Category: Transferase]]

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

OCA — Wed, 13 Jan 2016 18:56:53 GMT

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

←Older revision

Revision as of 18:56, 13 January 2016

OCA: New page: '''Unreleased structure''' The entry 5hes is ON HOLD until Paper Publication Authors: Mathea, S., Salah, E., Abdul Azeez, K.R., Tallant, C., Sorrell, F., Elkins, J., Shrestha, L., Burge...

OCA — Wed, 13 Jan 2016 18:56:51 GMT

New page: '''Unreleased structure''' The entry 5hes is ON HOLD until Paper Publication Authors: Mathea, S., Salah, E., Abdul Azeez, K.R., Tallant, C., Sorrell, F., Elkins, J., Shrestha, L., Burge...

New page

'''Unreleased structure'''

The entry 5hes is ON HOLD until Paper Publication

Authors: Mathea, S., Salah, E., Abdul Azeez, K.R., Tallant, C., Sorrell, F., Elkins, J., Shrestha, L., Burgess-Brown, N., von Delft, F., Arrowsmith, C.H., Edwards, A.M., Bountra, C., Knapp, S.

Description: Human leucine zipper-and sterile alpha motif-containing kinase (ZAK, MLT, HCCS-4, MRK, AZK, MLTK) in complex with vemurafenib
[[Category: Unreleased Structures]]
[[Category: Elkins, J]]
[[Category: Burgess-Brown, N]]
[[Category: Knapp, S]]
[[Category: Abdul Azeez, K.R]]
[[Category: Bountra, C]]
[[Category: Mathea, S]]
[[Category: Arrowsmith, C.H]]
[[Category: Shrestha, L]]
[[Category: Von Delft, F]]
[[Category: Edwards, A.M]]
[[Category: Tallant, C]]
[[Category: Salah, E]]
[[Category: Sorrell, F]]