6mc1

From Proteopedia

(Difference between revisions)

Current revision

Structure of MAP kinase phosphatase 5 in complex with 3,3-dimethyl-1-((9-(methylthio)-5,6-dihydrothieno[3,4-h]quinazolin-2-yl)thio)butan-2-one, an allosteric inhibitor

Structural highlights

6mc1 is a 6 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 2.7Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

DUS10_HUMAN Protein phosphatase involved in the inactivation of MAP kinases. Has a specificity for the MAPK11/MAPK12/MAPK13/MAPK14 subfamily.^[1]

Publication Abstract from PubMed

The mitogen-activated protein kinase (MAPK) phosphatases (MKPs) have been considered "undruggable," but their position as regulators of the MAPKs makes them promising therapeutic targets. MKP5 has been suggested as a potential target for the treatment of dystrophic muscle disease. Here, we identified an inhibitor of MKP5 using a p38alpha MAPK-derived, phosphopeptide-based small-molecule screen. We solved the structure of MKP5 in complex with this inhibitor, which revealed a previously undescribed allosteric binding pocket. Binding of the inhibitor to this pocket collapsed the MKP5 active site and was predicted to limit MAPK binding. Treatment with the inhibitor recapitulated the phenotype of MKP5 deficiency, resulting in activation of p38 MAPK and JNK. We demonstrated that MKP5 was required for TGF-beta1 signaling in muscle and that the inhibitor blocked TGF-beta1-mediated Smad2 phosphorylation. TGF-beta1 pathway antagonism has been proposed for the treatment of dystrophic muscle disease. Thus, allosteric inhibition of MKP5 represents a therapeutic strategy against dystrophic muscle disease.

An allosteric site on MKP5 reveals a strategy for small-molecule inhibition.,Gannam ZTK, Min K, Shillingford SR, Zhang L, Herrington J, Abriola L, Gareiss PC, Pantouris G, Tzouvelekis A, Kaminski N, Zhang X, Yu J, Jamali H, Ellman JA, Lolis E, Anderson KS, Bennett AM Sci Signal. 2020 Aug 25;13(646). pii: 13/646/eaba3043. doi:, 10.1126/scisignal.aba3043. PMID:32843541^[2]

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

References

↑ Zhang YY, Wu JW, Wang ZX. A Distinct Interaction Mode Revealed by the Crystal Structure of the Kinase p38alpha with the MAPK Binding Domain of the Phosphatase MKP5. Sci Signal. 2011 Dec 20;4(204):ra88. PMID:22375048 doi:10.1126/scisignal.2002241
↑ Gannam ZTK, Min K, Shillingford SR, Zhang L, Herrington J, Abriola L, Gareiss PC, Pantouris G, Tzouvelekis A, Kaminski N, Zhang X, Yu J, Jamali H, Ellman JA, Lolis E, Anderson KS, Bennett AM. An allosteric site on MKP5 reveals a strategy for small-molecule inhibition. Sci Signal. 2020 Aug 25;13(646). pii: 13/646/eaba3043. doi:, 10.1126/scisignal.aba3043. PMID:32843541 doi:http://dx.doi.org/10.1126/scisignal.aba3043

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/6mc1"

@@ Line 3: / Line 3: @@
 <StructureSection load='6mc1' size='340' side='right'caption='[[6mc1]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6mc1]] is a 6 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=6MC1 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6MC1 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6mc1]] is a 6 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=6MC1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6MC1 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CJA:3,3-dimethyl-1-{[9-(methylsulfanyl)-5,6-dihydrothieno[3,4-h]quinazolin-2-yl]sulfanyl}butan-2-one'>CJA</scene>, <scene name='pdbligand=DTT:2,3-DIHYDROXY-1,4-DITHIOBUTANE'>DTT</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]] 2.7&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DUSP10, MKP5 ([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=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CJA:3,3-dimethyl-1-{[9-(methylsulfanyl)-5,6-dihydrothieno[3,4-h]quinazolin-2-yl]sulfanyl}butan-2-one'>CJA</scene>, <scene name='pdbligand=DTT:2,3-DIHYDROXY-1,4-DITHIOBUTANE'>DTT</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=6mc1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mc1 OCA], [http://pdbe.org/6mc1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6mc1 RCSB], [http://www.ebi.ac.uk/pdbsum/6mc1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6mc1 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=6mc1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mc1 OCA], [https://pdbe.org/6mc1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6mc1 RCSB], [https://www.ebi.ac.uk/pdbsum/6mc1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6mc1 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/DUS10_HUMAN DUS10_HUMAN]] Protein phosphatase involved in the inactivation of MAP kinases. Has a specificity for the MAPK11/MAPK12/MAPK13/MAPK14 subfamily.<ref>PMID:22375048</ref>
+[https://www.uniprot.org/uniprot/DUS10_HUMAN DUS10_HUMAN] Protein phosphatase involved in the inactivation of MAP kinases. Has a specificity for the MAPK11/MAPK12/MAPK13/MAPK14 subfamily.<ref>PMID:22375048</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 19: / Line 19: @@
 </div>
 <div class="pdbe-citations 6mc1" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[MAP kinase phosphatase|MAP kinase phosphatase]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Anderson, K S]]
+[[Category: Anderson KS]]
-[[Category: Bennett, A M]]
+[[Category: Bennett AM]]
-[[Category: Gannam, Z T.K]]
+[[Category: Gannam ZTK]]
-[[Category: Lolis, E]]
+[[Category: Lolis E]]
-[[Category: Dual specificity phosphatase]]
-[[Category: Hydrolase-hydrolase inhibitor complex]]
-[[Category: Phosphatase]]
-[[Category: Phosphatase-inhibitor complex]]
-[[Category: Protein-tyrosine phosphatase]]

6mc1

From Proteopedia

Current revision

Structure of MAP kinase phosphatase 5 in complex with 3,3-dimethyl-1-((9-(methylthio)-5,6-dihydrothieno[3,4-h]quinazolin-2-yl)thio)butan-2-one, an allosteric inhibitor

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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