Selective Small Molecule Compounds Increase BMP-2 Responsiveness by Inhibiting Smurf1-mediated Smad1/5 Degradation
Copyright policy )Selective Small Molecule Compounds Increase BMP-2 Responsiveness by Inhibiting Smurf1-mediated Smad1/5 Degradation
AbstractThe ubiquitin ligase Smad ubiquitination regulatory factor-1 (Smurf1) negatively regulates bone morphogenetic protein (BMP) pathway by ubiquitinating certain signal components for degradation. Thus, it can be an eligible pharmacological target for increasing BMP signal responsiveness. We established a strategy to discover small molecule compounds that block the WW1 domain of Smurf1 from interacting with Smad1/5 by structure based virtual screening, molecular experimental examination and cytological efficacy evaluation. Our selected hits could reserve the protein level of Smad1/5 from degradation by interrupting Smurf1-Smad1/5 interaction and inhibiting Smurf1 mediated ubiquitination of Smad1/5. Further, these compounds increased BMP-2 signal responsiveness and the expression of certain downstream genes, enhanced the osteoblastic activity of myoblasts and osteoblasts. Our work indicates targeting Smurf1 for inhibition could be an accessible strategy to discover BMP-sensitizers that might be applied in future clinical treatments of bone disorders such as osteopenia.
- State Key Laboratory of Proteomics China (People's Republic of)
- Dalian Medical University China (People's Republic of)
- Academy of Military Medical Sciences China (People's Republic of)
- Shihezi University China (People's Republic of)
- Beijing Proteome Research Center China (People's Republic of)
Smad5 Protein, Osteoblasts, Ubiquitin-Protein Ligases, Ubiquitination, Bone Morphogenetic Protein 2, Article, Protein Structure, Tertiary, Smad1 Protein, Myoblasts, Small Molecule Libraries, HEK293 Cells, Proteolysis, Humans, Protein Interaction Domains and Motifs, Cells, Cultured, Signal Transduction
Smad5 Protein, Osteoblasts, Ubiquitin-Protein Ligases, Ubiquitination, Bone Morphogenetic Protein 2, Article, Protein Structure, Tertiary, Smad1 Protein, Myoblasts, Small Molecule Libraries, HEK293 Cells, Proteolysis, Humans, Protein Interaction Domains and Motifs, Cells, Cultured, Signal Transduction
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