ArticleJournal of molecular biology2014
Specific inhibition of p97/VCP ATPase and kinetic analysis demonstrate interaction between D1 and D2 ATPase domains.
Article in Journal of molecular biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 79 papers.
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Who cites it
79 citing papers in PubMed, 118 citations in OpenAlex.
- 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
- The vacuolar tauopathy-associated mutation D395G confers redox sensitivity to p97/VCP.bioRxiv : the preprint server for biology · 2026Article
- Harnessing p97/VCP: A Transformative AAA+ ATPase Target for Next-Generation Cancer Therapeutics.Cancers · 2025Review
- A genome-scale drug discovery pipeline uncovers therapeutic targets and a unique p97 allosteric binding site inProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Structural basis of VCP-VCPIP1-p47 ternary complex in Golgi maintenance.Nature communications · 2025Article
- A genome-scale drug discovery pipeline uncovers new therapeutic targets and a unique p97 allosteric binding site inbioRxiv : the preprint server for biology · 2025Article
- Time-resolved interactome profiling deconvolutes secretory protein quality control dynamics.Molecular systems biology · 2024Article
- Mechanism of allosteric inhibition of human p97/VCP ATPase and its disease mutant by triazole inhibitors.Communications chemistry · 2024Article
- VCP activator reverses nuclear proteostasis defects and enhances TDP-43 aggregate clearance in multisystem proteinopathy models.The Journal of clinical investigation · 2024Article
- Valosin-Containing Protein (VCP): A Review of Its Diverse Molecular Functions and Clinical Phenotypes.International journal of molecular sciences · 2024Review
- Advances in the study of protein folding and endoplasmic reticulum-associated degradation in mammal cells.Journal of Zhejiang University. Science. B · 2024Review
- Valosin-Containing Protein (VCP)/p97 Oligomerization.Sub-cellular biochemistry · 2024Review
- The p97/VCP adaptor UBXD1 drives AAA+ remodeling and ring opening through multi-domain tethered interactions.Nature structural & molecular biology · 2023Article
- An autosomal-dominant childhood-onset disorder associated with pathogenic variants in VCP.American journal of human genetics · 2023Article
- Clinical Classification of Variants in the Valosin-Containing Protein Gene Associated With Multisystem Proteinopathy.Neurology. Genetics · 2023Article
- Recent Advances in Chemotherapeutics for Leishmaniasis: Importance of the Cellular Biochemistry of the Parasite and Its Molecular Interaction with the Host.Pathogens (Basel, Switzerland) · 2023Review
- Molecular Mechanisms Driving and Regulating the AAA+ ATPase VCP/p97, an Important Therapeutic Target for Treating Cancer, Neurological and Infectious Diseases.Biomolecules · 2023Review
- Bcs1, a novel target for fungicide.Frontiers in chemistry · 2023Review
- Discovery of novel benzylquinazoline molecules as p97/VCP inhibitors.Frontiers in pharmacology · 2023Article
19 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
10 authors at 6 institutions in 1 country.
Funding
Abstract
The p97 AAA (ATPase associated with diverse cellular activities), also called VCP (valosin-containing protein), is an important therapeutic target for cancer and neurodegenerative diseases. p97 forms a hexamer composed of two AAA domains (D1 and D2) that form two stacked rings and an N-terminal domain that binds numerous cofactor proteins. The interplay between the three domains in p97 is complex, and a deeper biochemical understanding is needed in order to design selective p97 inhibitors as therapeutic agents. It is clear that the D2 ATPase domain hydrolyzes ATP in vitro, but whether D1 contributes to ATPase activity is controversial. Here, we use Walker A and B mutants to demonstrate that D1 is capable of hydrolyzing ATP and show for the first time that nucleotide binding in the D2 domain increases the catalytic efficiency (kcat/Km) of D1 ATP hydrolysis 280-fold, by increasing kcat 7-fold and decreasing Km about 40-fold. We further show that an ND1 construct lacking D2 but including the linker between D1 and D2 is catalytically active, resolving a conflict in the literature. Applying enzymatic observations to small-molecule inhibitors, we show that four p97 inhibitors (DBeQ, ML240, ML241, and NMS-873) have differential responses to Walker A and B mutations, to disease-causing IBMPFD mutations, and to the presence of the N domain binding cofactor protein p47. These differential effects provide the first evidence that p97 cofactors and disease mutations can alter p97 inhibitor potency and suggest the possibility of developing context-dependent inhibitors of p97.
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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.