6jut

From Proteopedia

(Difference between revisions)

Revision as of 06:13, 24 July 2019

Crystal structure of ZAK in complex with compound 6k

Structural highlights

6jut is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Activity:	Mitogen-activated protein kinase kinase kinase, with EC number 2.7.11.25
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[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'.^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

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.

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^[7]

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

References

↑ Liu TC, Huang CJ, Chu YC, Wei CC, Chou CC, Chou MY, Chou CK, Yang JJ. Cloning and expression of ZAK, a mixed lineage kinase-like protein containing a leucine-zipper and a sterile-alpha motif. Biochem Biophys Res Commun. 2000 Aug 11;274(3):811-6. PMID:10924358 doi:http://dx.doi.org/10.1006/bbrc.2000.3236
↑ Gotoh I, Adachi M, Nishida E. Identification and characterization of a novel MAP kinase kinase kinase, MLTK. J Biol Chem. 2001 Feb 9;276(6):4276-86. Epub 2000 Oct 19. PMID:11042189 doi:http://dx.doi.org/10.1074/jbc.M008595200
↑ Gross EA, Callow MG, Waldbaum L, Thomas S, Ruggieri R. MRK, a mixed lineage kinase-related molecule that plays a role in gamma-radiation-induced cell cycle arrest. J Biol Chem. 2002 Apr 19;277(16):13873-82. Epub 2002 Feb 8. PMID:11836244 doi:http://dx.doi.org/10.1074/jbc.M111994200
↑ Cho YY, Bode AM, Mizuno H, Choi BY, Choi HS, Dong Z. A novel role for mixed-lineage kinase-like mitogen-activated protein triple kinase alpha in neoplastic cell transformation and tumor development. Cancer Res. 2004 Jun 1;64(11):3855-64. PMID:15172994 doi:http://dx.doi.org/10.1158/0008-5472.CAN-04-0201
↑ Tosti E, Waldbaum L, Warshaw G, Gross EA, Ruggieri R. The stress kinase MRK contributes to regulation of DNA damage checkpoints through a p38gamma-independent pathway. J Biol Chem. 2004 Nov 12;279(46):47652-60. Epub 2004 Sep 1. PMID:15342622 doi:http://dx.doi.org/10.1074/jbc.M409961200
↑ Choi HS, Choi BY, Cho YY, Zhu F, Bode AM, Dong Z. Phosphorylation of Ser28 in histone H3 mediated by mixed lineage kinase-like mitogen-activated protein triple kinase alpha. J Biol Chem. 2005 Apr 8;280(14):13545-53. Epub 2005 Jan 31. PMID:15684425 doi:http://dx.doi.org/M410521200
↑ Yang J, Shibu MA, Kong L, Luo J, BadrealamKhan F, Huang Y, Tu ZC, Yun CH, Huang CY, Ding K, Lu X. Design, Synthesis, and Structure-Activity Relationships of 1,2,3-Triazole Benzenesulfonamides as New Selective Leucine-Zipper and Sterile-alpha Motif Kinase (ZAK) Inhibitors. J Med Chem. 2019 Jun 17. doi: 10.1021/acs.jmedchem.9b00664. PMID:31244114 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b00664

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6jut"

@@ 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]]

6jut

From Proteopedia

Revision as of 06:13, 24 July 2019

Crystal structure of ZAK in complex with compound 6k

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox