6mc1 | pdb_00006mc1

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

spinqualitylabelsall models 6mc1, resolution 2.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D 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: ACT, CJA, DTT 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also MAP kinase phosphatase

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