6mc1

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.