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5gtj

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CRYSTAL STRUCTURE OF CATALYTICALLY ACTIVE FORM OF HUMAN DUSP26

Structural highlights

5gtj is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

DUS26_HUMAN Inactivates MAPK1 and MAPK3 which leads to dephosphorylation of heat shock factor protein 4 and a reduction in its DNA-binding activity. Inhibits MAP kinase p38 by dephosphorylating it and inhibits p38-mediated apoptosis in anaplastic thyroid cancer cells. Can also induce activation of MAP kinase p38 and c-Jun N-terminal kinase (JNK).^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Human dual-specificity phosphatase 26 (DUSP26) is a novel target for anticancer therapy because its dephosphorylation of the p53 tumor suppressor regulates the apoptosis of cancer cells. DUSP26 inhibition results in neuroblastoma cell cytotoxicity through p53-mediated apoptosis. Despite the previous structural studies of DUSP26 catalytic domain (residues 61-211, DUSP26-C), the high-resolution structure of its catalytically active form has not been resolved. In this study, we determined the crystal structure of a catalytically active form of DUSP26 (residues 39-211, DUSP26-N) with an additional N-terminal region at 2.0 A resolution. Unlike the C-terminal domain-swapped dimeric structure of DUSP26-C, the DUSP26-N (C152S) monomer adopts a fold-back conformation of the C-terminal alpha8-helix and has an additional alpha1-helix in the N-terminal region. Consistent with the canonically active conformation of its protein tyrosine phosphate-binding loop (PTP loop) observed in the structure, the phosphatase assay results demonstrated that DUSP26-N has significantly higher catalytic activity than DUSP26-C. Furthermore, size exclusion chromatography-multiangle laser scattering (SEC-MALS) measurements showed that DUSP26-N (C152S) exists as a monomer in solution. Notably, the crystal structure of DUSP26-N (C152S) revealed that the N-terminal region of DUSP26-N (C152S) serves a scaffolding role by positioning the surrounding alpha7-alpha8 loop for interaction with the PTP-loop through formation of an extensive hydrogen bond network, which seems to be critical in making the PTP-loop conformation competent for phosphatase activity. Our study provides the first high-resolution structure of a catalytically active form of DUSP26, which will contribute to the structure-based rational design of novel DUSP26-targeting anticancer therapeutics.

Structural Insight into the Critical Role of the N-Terminal Region in the Catalytic Activity of Dual-Specificity Phosphatase 26.,Won EY, Lee SO, Lee DH, Lee D, Bae KH, Lee SC, Kim SJ, Chi SW PLoS One. 2016 Sep 1;11(9):e0162115. doi: 10.1371/journal.pone.0162115., eCollection 2016. PMID:27583453^[5]

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

References

↑ Vasudevan SA, Skoko J, Wang K, Burlingame SM, Patel PN, Lazo JS, Nuchtern JG, Yang J. MKP-8, a novel MAPK phosphatase that inhibits p38 kinase. Biochem Biophys Res Commun. 2005 May 6;330(2):511-8. PMID:15796912 doi:10.1016/j.bbrc.2005.03.028
↑ Yu W, Imoto I, Inoue J, Onda M, Emi M, Inazawa J. A novel amplification target, DUSP26, promotes anaplastic thyroid cancer cell growth by inhibiting p38 MAPK activity. Oncogene. 2007 Feb 22;26(8):1178-87. Epub 2006 Aug 21. PMID:16924234 doi:10.1038/sj.onc.1209899
↑ Takagaki K, Shima H, Tanuma N, Nomura M, Satoh T, Watanabe M, Kikuchi K. Characterization of a novel low-molecular-mass dual specificity phosphatase-4 (LDP-4) expressed in brain. Mol Cell Biochem. 2007 Feb;296(1-2):177-84. Epub 2006 Sep 26. PMID:17001450 doi:10.1007/s11010-006-9313-5
↑ Hu Y, Mivechi NF. Association and regulation of heat shock transcription factor 4b with both extracellular signal-regulated kinase mitogen-activated protein kinase and dual-specificity tyrosine phosphatase DUSP26. Mol Cell Biol. 2006 Apr;26(8):3282-94. PMID:16581800 doi:26/8/3282
↑ Won EY, Lee SO, Lee DH, Lee D, Bae KH, Lee SC, Kim SJ, Chi SW. Structural Insight into the Critical Role of the N-Terminal Region in the Catalytic Activity of Dual-Specificity Phosphatase 26. PLoS One. 2016 Sep 1;11(9):e0162115. doi: 10.1371/journal.pone.0162115., eCollection 2016. PMID:27583453 doi:http://dx.doi.org/10.1371/journal.pone.0162115

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5gtj"

Categories: Homo sapiens | Large Structures | Chi S-W | Kim SJ | Won E-Y

@@ Line 3: / Line 3: @@
 <StructureSection load='5gtj' size='340' side='right'caption='[[5gtj]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5gtj]] is a 4 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=5GTJ OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5GTJ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5gtj]] 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=5GTJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5GTJ FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DUSP26, DUSP24, LDP4, MKP8, NATA1, SKRP3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></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=5gtj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5gtj OCA], [http://pdbe.org/5gtj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5gtj RCSB], [http://www.ebi.ac.uk/pdbsum/5gtj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5gtj ProSAT]</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=5gtj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5gtj OCA], [https://pdbe.org/5gtj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5gtj RCSB], [https://www.ebi.ac.uk/pdbsum/5gtj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5gtj ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/DUS26_HUMAN DUS26_HUMAN]] Inactivates MAPK1 and MAPK3 which leads to dephosphorylation of heat shock factor protein 4 and a reduction in its DNA-binding activity. Inhibits MAP kinase p38 by dephosphorylating it and inhibits p38-mediated apoptosis in anaplastic thyroid cancer cells. Can also induce activation of MAP kinase p38 and c-Jun N-terminal kinase (JNK).<ref>PMID:15796912</ref> <ref>PMID:16924234</ref> <ref>PMID:17001450</ref> <ref>PMID:16581800</ref>
+[https://www.uniprot.org/uniprot/DUS26_HUMAN DUS26_HUMAN] Inactivates MAPK1 and MAPK3 which leads to dephosphorylation of heat shock factor protein 4 and a reduction in its DNA-binding activity. Inhibits MAP kinase p38 by dephosphorylating it and inhibits p38-mediated apoptosis in anaplastic thyroid cancer cells. Can also induce activation of MAP kinase p38 and c-Jun N-terminal kinase (JNK).<ref>PMID:15796912</ref> <ref>PMID:16924234</ref> <ref>PMID:17001450</ref> <ref>PMID:16581800</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 27: / Line 27: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Chi, S W]]
+[[Category: Chi S-W]]
-[[Category: Kim, S J]]
+[[Category: Kim SJ]]
-[[Category: Won, E Y]]
+[[Category: Won E-Y]]
-[[Category: Active form]]
-[[Category: Hydrolase]]

5gtj

From Proteopedia

Current revision

CRYSTAL STRUCTURE OF CATALYTICALLY ACTIVE FORM OF HUMAN DUSP26

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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