An allosteric site on MKP5 reveals a strategy for small-molecule inhibition.
Allosteric Site
/ genetics
Amino Acid Sequence
Animals
Cell Differentiation
/ drug effects
Cell Line
Dual-Specificity Phosphatases
/ antagonists & inhibitors
Enzyme Inhibitors
/ chemistry
Female
High-Throughput Screening Assays
/ methods
Humans
Kinetics
Mice
Mice, Knockout
Mitogen-Activated Protein Kinase Phosphatases
/ antagonists & inhibitors
Myoblasts
/ cytology
Protein Binding
/ drug effects
Sequence Homology, Amino Acid
Signal Transduction
/ drug effects
Small Molecule Libraries
/ chemistry
Journal
Science signaling
ISSN: 1937-9145
Titre abrégé: Sci Signal
Pays: United States
ID NLM: 101465400
Informations de publication
Date de publication:
25 08 2020
25 08 2020
Historique:
entrez:
27
8
2020
pubmed:
28
8
2020
medline:
30
10
2021
Statut:
epublish
Résumé
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 p38α 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-β1 signaling in muscle and that the inhibitor blocked TGF-β1-mediated Smad2 phosphorylation. TGF-β1 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.
Identifiants
pubmed: 32843541
pii: 13/646/eaba3043
doi: 10.1126/scisignal.aba3043
pmc: PMC7569488
mid: NIHMS1629146
pii:
doi:
Substances chimiques
Enzyme Inhibitors
0
Small Molecule Libraries
0
DUSP10 protein, human
EC 3.1.3.16
Mitogen-Activated Protein Kinase Phosphatases
EC 3.1.3.16
Dual-Specificity Phosphatases
EC 3.1.3.48
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIAID NIH HHS
ID : T32 AI055403
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM122473
Pays : United States
Organisme : NIDDK NIH HHS
ID : P01 DK057751
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM124165
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL153599
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR066003
Pays : United States
Informations de copyright
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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