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Updated: Mar 8, 2026
07:58
In-vitro Reconstitution of Bacterial Ubiquitination and VCP/p97-mediated Elimination
Published on: January 2, 2026
520
Development and Structural Characterization of UTE-156, a Covalent Inhibitor of the VCP/p97 AAA+ ATPase
Daniela Tamayo-Jaramillo1, Subramanya Hegde2, Xuan Jia1
1Department of Biochemistry, University of Utah, Salt Lake City, Utah, USA.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|March 7, 2026
Summary
Researchers developed UTE-156, a novel covalent inhibitor targeting the valosin-containing protein (VCP/p97) involved in protein homeostasis. This chemical probe effectively inhibits VCP activity, offering a new tool for studying its role in disease.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Valosin-containing protein (VCP/p97), an AAA+ ATPase, is crucial for protein homeostasis and substrate remodeling.
- VCP dysregulation is implicated in neurodegenerative diseases and cancer, identifying it as a key therapeutic target.
Purpose of the Study:
- To develop and characterize UTE-156, a novel covalent small-molecule inhibitor of VCP.
- To investigate the mechanism of action and structural basis of VCP inhibition by UTE-156.
Main Methods:
- Synthesis and biochemical characterization of UTE-156.
- Cryo-electron microscopy (cryo-EM) for structural analysis.
- Cell-based assays to evaluate VCP inhibition.
Main Results:
- UTE-156 covalently modifies Cys522 in the VCP D2 ATPase domain, inhibiting its activity.
- Cryo-EM structures show UTE-156 binding to the nucleotide-binding site, blocking ATP access.
- UTE-156 exhibits potent inhibition but has limitations in solubility and metabolic stability.
Conclusions:
- UTE-156 serves as a valuable chemical probe for dissecting VCP function.
- The findings provide a foundation for developing optimized covalent VCP inhibitors for therapeutic applications.
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