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TitleDevelopment and Structural Characterization of UTE-156, a Covalent Inhibitor of the VCP/p97 AAA+ ATPase.
Journal, issue, pagesAdv Sci (Weinh), Page e20545, Year 2026
Publish dateMar 7, 2026
AuthorsDaniela Tamayo-Jaramillo / Subramanya Hegde / Xuan Jia / Kimberly Coffman / Hariprasad Vankayalapati / David Bearss / Kevin B Jones / Alex W Stark / Peter S Shen /
PubMed AbstractThe AAA+ ATPase valosin-containing protein (VCP/p97) is a central regulator of protein homeostasis that is well characterized for its role in extracting and remodeling ubiquitinated substrates. ...The AAA+ ATPase valosin-containing protein (VCP/p97) is a central regulator of protein homeostasis that is well characterized for its role in extracting and remodeling ubiquitinated substrates. Dysregulation of VCP activity contributes to the pathogenesis of neurodegenerative diseases and cancer, making it an important therapeutic target. Here, we report the development and characterization of UTE-156, a novel covalent small-molecule inhibitor that modifies Cys522 within the D2 ATPase domain of VCP. UTE-156 potently inhibits VCP ATPase activity, while losing activity against a C522A mutant, supporting a covalent mechanism of action. High-resolution cryo-electron microscopy (cryo-EM) structures reveal that UTE-156 occupies the D2 nucleotide-binding site, sterically blocking ATP binding and inducing conformational remodeling of the pocket. Biochemical and cell-based assays demonstrate strong inhibitory potency but limited solubility and rapid metabolic turnover. These pharmacochemical limitations preclude immediate therapeutic use but underscore its value as a chemical probe. Together, these findings establish UTE-156 as a powerful tool for dissecting VCP function and provide a framework for future optimization of covalent modulators of protein homeostasis.
External linksAdv Sci (Weinh) / PubMed:41793187
MethodsEM (single particle)
Resolution2.13 - 2.8 Å
Structure data

73285

9yp6

EMDB-73285, PDB-9yp6:
Structure of human VCP/p97 hexamer bound to ADP and UTE-156
Method: EM (single particle) / Resolution: 2.8 Å

73287

9yp8

EMDB-73287, PDB-9yp8:
Structure of human VCP/p97 dodecamer bound to ADP and UTE-156
Method: EM (single particle) / Resolution: 2.4 Å

75391

10qq

EMDB-75391, PDB-10qq:
Structure of human VCP/p97 dodecamer bound to ADP (DMSO control)
Method: EM (single particle) / Resolution: 2.13 Å

75392

10qr

EMDB-75392, PDB-10qr:
Structure of human VCP/p97 hexamer bound to ADP (DMSO control)
Method: EM (single particle) / Resolution: 2.3 Å

Chemicals

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

ChemComp-MG:
Unknown entry

ChemComp-HOH:
WATER

PDB-1cyl:
ASPECTS OF RECEPTOR BINDING AND SIGNALLING OF INTERLEUKIN-4 INVESTIGATED BY SITE-DIRECTED MUTAGENESIS AND NMR SPECTROSCOPY

Source
  • homo sapiens (human)
KeywordsCHAPERONE / VCP / p97 / dodecamer / hexamer / ADP / inhibitor / UTE-156 / covalent

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