ArticleNature communications2021
Seesaw conformations of Npl4 in the human p97 complex and the inhibitory mechanism of a disulfiram derivative.
Article in Nature communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 68 papers, 1 of them a synthesis that pooled it.
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Who cites it
68 citing papers in PubMed, 1 synthesis or guideline pooled it, 101 citations in OpenAlex.
- Revolutionizing breast cancer treatment: Harnessing the related mechanisms and drugs for regulated cell death (Review).International journal of oncology · 2024Pooled it
- Disulfiram ameliorates nonalcoholic steatohepatitis by modulating the gut microbiota and bile acid metabolism.Nature communications · 2022Trial
- VCP at the crossroads of UPS and autophagy in cancer.Genes & diseases · 2027Review
- Multifunctional Metal-Coordinated Hydrogels: Controlled Synthesis and Advances in Anti-Inflammatory, Anticancer, and Antibacterial Applications.ACS omega · 2026Review
- Copper, cuproptosis, and cancer: biology concepts of a novel cell death.Apoptosis : an international journal on programmed cell death · 2026Review
- FAF1 and FAF2 enhance unfolding by p97-UFD1-NPL4 complex enabling rational design of p97 activators.The EMBO journal · 2026Article
- FAF1 cofactor enhances UFD1/NPL4-p97 unfolding efficiency across ubiquitin chain lengths independent of SUMO2.bioRxiv : the preprint server for biology · 2026Article
- Disulfiram Alleviates Metabolic Dysfunction-Associated Steatohepatitis in Mice via Inhibiting Aurora Kinase A and Restoring Autophagy.Antioxidants (Basel, Switzerland) · 2026Article
- Beyond apoptosis: nanomedicine enabled reprogramming of tumor cell death for next-generation radiosensitization.Journal of nanobiotechnology · 2026Review
- Copper homeostasis and cuproptosis: molecular mechanisms and therapeutic opportunities.Molecular biomedicine · 2026Review
- Npl4 decodes polyubiquitin length and gates D1-D2 coupling in human VCP/p97.Research square · 2026Article
- Npl4 decodes polyubiquitin length and gates D1-D2 coupling in human VCP/p97.bioRxiv : the preprint server for biology · 2026Article
- CuET promotes cuproptosis and ferroptosis of lung cancer cells by interacting directly with polyunsaturated phospholipids.iScience · 2026Article
- The deubiquitinating enzyme Otu1 releases substrates from the conserved initiation complex of the Cdc48/p97 ATPase for proteasomal degradation.Scientific reports · 2026Article
- The accessory adapters FAF1, FAF2, and UBXN7 accelerate proteasomal degradation by increasing prior p97-mediated substrate unfolding.Science advances · 2026Article
- Cryo-EM structural analyses reveal plant-specific adaptations of the CDC48 unfoldase.Plant communications · 2026Article
- Differential cytotoxicity mechanisms of copper complexed with disulfiram for combination chemotherapy in human endometrial cancer cells.Frontiers in oncology · 2026Article
- Unveiling the metal-driven death: ferroptosis and cuproptosis in leukemia.European journal of medical research · 2025Review
- Navigating Transition Metal-Dependent Cell Death: Mechanisms, Crosstalk, and Future Directions.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- Specific proteolysis mediated by a p97-directed proteolysis-targeting chimera (p97-PROTAC).eLife · 2025Article
8 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
9 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
p97, also known as valosin-containing protein (VCP) or Cdc48, plays a central role in cellular protein homeostasis. Human p97 mutations are associated with several neurodegenerative diseases. Targeting p97 and its cofactors is a strategy for cancer drug development. Despite significant structural insights into the fungal homolog Cdc48, little is known about how human p97 interacts with its cofactors. Recently, the anti-alcohol abuse drug disulfiram was found to target cancer through Npl4, a cofactor of p97, but the molecular mechanism remains elusive. Here, using single-particle cryo-electron microscopy (cryo-EM), we uncovered three Npl4 conformational states in complex with human p97 before ATP hydrolysis. The motion of Npl4 results from its zinc finger motifs interacting with the N domain of p97, which is essential for the unfolding activity of p97. In vitro and cell-based assays showed that the disulfiram derivative bis-(diethyldithiocarbamate)-copper (CuET) can bypass the copper transporter system and inhibit the function of p97 in the cytoplasm by releasing cupric ions under oxidative conditions, which disrupt the zinc finger motifs of Npl4, locking the essential conformational switch of the complex.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.