6jut: Difference between revisions

Line 1:

~~'''Unreleased structure'''~~

~~The entry~~ 6jut is ~~ON HOLD~~ ~~until Paper~~ Publication

==Crystal structure of ZAK in complex with compound 6k==

== Structural highlights ==

<table><tr><td colspan='2'>[[6jut]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6JUT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6JUT FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=C9O:~{N}-[2,4-bis(fluoranyl)-3-[4-(3-methoxy-1~{H}-pyrazolo[3,4-b]pyridin-5-yl)-1,2,3-triazol-1-yl]phenyl]-3-bromanyl-benzenesulfonamide'>C9O</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=6jut FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jut OCA], [http://pdbe.org/6jut PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6jut RCSB], [http://www.ebi.ac.uk/pdbsum/6jut PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6jut ProSAT]</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>

== Publication Abstract from PubMed ==

ZAK is a new promising target for discovery of drugs with activity against antihypertrophic cardiomyopathy (HCM). A series of 1,2,3-triazole benzenesulfonamides were designed and synthesized as selective ZAK inhibitors. One of these compounds, 6p binds tightly to ZAK protein ( Kd = 8.0 nM) and potently suppresses the kinase function of ZAK with single-digit nM (IC50 = 4.0 nM) and exhibits excellent selectivity in a KINOMEscan screening platform against a panel of 403 wild-type kinases. This compound dose dependently blocks p38/GATA-4 and JNK/c-Jun signaling and demonstrates promising in vivo anti-HCM efficacy upon oral administration in a spontaneous hypertensive rat (SHR) model. Compound 6p may serve as a lead compound for new anti-HCM drug discovery.

~~Authors: Kong~~, L.L., Yun, C.H.

Design, Synthesis, and Structure-Activity Relationships of 1,2,3-Triazole Benzenesulfonamides as New Selective Leucine-Zipper and Sterile-alpha Motif Kinase (ZAK) Inhibitors.,Yang J, Shibu MA, Kong L, Luo J, BadrealamKhan F, Huang Y, Tu ZC, Yun CH, Huang CY, Ding K, Lu X J Med Chem. 2019 Jun 17. doi: 10.1021/acs.jmedchem.9b00664. PMID:31244114<ref>PMID:31244114</ref>

~~Description~~: ~~Crystal structure of ZAK in complex with compound 6k~~

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>

[[Category: ~~Unreleased~~ Structures]]

</div>

[[Category: Kong, L.L]]

[[Category: Yun, C.H]]

== References ==

__TOC__

</StructureSection>

[[Category: Large Structures]]

[[Category: Mitogen-activated protein kinase kinase kinase]]

[[Category: Kong, L L]]

[[Category: Yun, C H]]

[[Category: Inhibitor]]

[[Category: Structural protein]]

[[Category: Zak]]

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@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6jut is ON HOLD  until Paper Publication
+==Crystal structure of ZAK in complex with compound 6k==
+<StructureSection load='6jut' size='340' side='right'caption='[[6jut]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6jut]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6JUT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6JUT FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=C9O:~{N}-[2,4-bis(fluoranyl)-3-[4-(3-methoxy-1~{H}-pyrazolo[3,4-b]pyridin-5-yl)-1,2,3-triazol-1-yl]phenyl]-3-bromanyl-benzenesulfonamide'>C9O</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=6jut FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jut OCA], [http://pdbe.org/6jut PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6jut RCSB], [http://www.ebi.ac.uk/pdbsum/6jut PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6jut ProSAT]</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 ==
+ZAK is a new promising target for discovery of drugs with activity against antihypertrophic cardiomyopathy (HCM). A series of 1,2,3-triazole benzenesulfonamides were designed and synthesized as selective ZAK inhibitors. One of these compounds, 6p binds tightly to ZAK protein ( Kd = 8.0 nM) and potently suppresses the kinase function of ZAK with single-digit nM (IC50 = 4.0 nM) and exhibits excellent selectivity in a KINOMEscan screening platform against a panel of 403 wild-type kinases. This compound dose dependently blocks p38/GATA-4 and JNK/c-Jun signaling and demonstrates promising in vivo anti-HCM efficacy upon oral administration in a spontaneous hypertensive rat (SHR) model. Compound 6p may serve as a lead compound for new anti-HCM drug discovery.
-Authors: Kong, L.L., Yun, C.H.
+Design, Synthesis, and Structure-Activity Relationships of 1,2,3-Triazole Benzenesulfonamides as New Selective Leucine-Zipper and Sterile-alpha Motif Kinase (ZAK) Inhibitors.,Yang J, Shibu MA, Kong L, Luo J, BadrealamKhan F, Huang Y, Tu ZC, Yun CH, Huang CY, Ding K, Lu X J Med Chem. 2019 Jun 17. doi: 10.1021/acs.jmedchem.9b00664. PMID:31244114<ref>PMID:31244114</ref>
-Description: Crystal structure of ZAK in complex with compound 6k
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Kong, L.L]]
+<div class="pdbe-citations 6jut" style="background-color:#fffaf0;"></div>
-[[Category: Yun, C.H]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Large Structures]]
+[[Category: Mitogen-activated protein kinase kinase kinase]]
+[[Category: Kong, L L]]
+[[Category: Yun, C H]]
+[[Category: Inhibitor]]
+[[Category: Structural protein]]
+[[Category: Zak]]