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- PDB-10qq: Structure of human VCP/p97 dodecamer bound to ADP (DMSO control) -

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Basic information

Entry
Database: PDB / ID: 10qq
TitleStructure of human VCP/p97 dodecamer bound to ADP (DMSO control)
ComponentsTransitional endoplasmic reticulum ATPase
KeywordsCHAPERONE / VCP / p97 / dodecamer
Function / homology
Function and homology information


flavin adenine dinucleotide catabolic process / VCP-NSFL1C complex / endoplasmic reticulum stress-induced pre-emptive quality control / endosome to lysosome transport via multivesicular body sorting pathway / BAT3 complex binding / cellular response to arsenite ion / cytoplasmic ubiquitin ligase complex / Derlin-1 retrotranslocation complex / positive regulation of protein K63-linked deubiquitination / protein-DNA covalent cross-linking repair ...flavin adenine dinucleotide catabolic process / VCP-NSFL1C complex / endoplasmic reticulum stress-induced pre-emptive quality control / endosome to lysosome transport via multivesicular body sorting pathway / BAT3 complex binding / cellular response to arsenite ion / cytoplasmic ubiquitin ligase complex / Derlin-1 retrotranslocation complex / positive regulation of protein K63-linked deubiquitination / protein-DNA covalent cross-linking repair / deubiquitinase activator activity / positive regulation of oxidative phosphorylation / cytoplasm protein quality control / regulation of protein localization to chromatin / ubiquitin-modified protein reader activity / cellular response to misfolded protein / mitotic spindle disassembly / VCP-NPL4-UFD1 AAA ATPase complex / positive regulation of mitochondrial membrane potential / vesicle-fusing ATPase / K48-linked polyubiquitin modification-dependent protein binding / NAD+ metabolic process / regulation of aerobic respiration / retrograde protein transport, ER to cytosol / stress granule disassembly / ATPase complex / ubiquitin-specific protease binding / regulation of synapse organization / polyubiquitin modification-dependent protein binding / positive regulation of ATP biosynthetic process / ubiquitin-like protein ligase binding / intracellular membrane-bounded organelle / RHOH GTPase cycle / autophagosome maturation / MHC class I protein binding / HSF1 activation / endoplasmic reticulum to Golgi vesicle-mediated transport / negative regulation of hippo signaling / mitophagy / interstrand cross-link repair / ATP metabolic process / proteasome complex / protein unfolding / endoplasmic reticulum unfolded protein response / ribosome-associated ubiquitin-dependent protein catabolic process / Attachment and Entry / ERAD pathway / Protein methylation / translesion synthesis / negative regulation of smoothened signaling pathway / viral genome replication / negative regulation of protein localization to chromatin / macroautophagy / rescue of stalled cytosolic ribosome / lipid droplet / Josephin domain DUBs / autophagy / establishment of protein localization / proteasomal protein catabolic process / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / positive regulation of protein-containing complex assembly / positive regulation of non-canonical NF-kappaB signal transduction / ADP binding / Hh mutants are degraded by ERAD / Dengue Virus Genome Translation and Replication / Translesion Synthesis by POLH / Hedgehog ligand biogenesis / Defective CFTR causes cystic fibrosis / AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274) / ABC-family protein mediated transport / cytoplasmic stress granule / Ribosome Quality Control (RQC) complex extracts and degrades nascent peptide / double-strand break repair / Aggrephagy / positive regulation of canonical Wnt signaling pathway / positive regulation of protein catabolic process / azurophil granule lumen / Ovarian tumor domain proteases / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / KEAP1-NFE2L2 pathway / site of double-strand break / cellular response to heat / E3 ubiquitin ligases ubiquitinate target proteins / Neddylation / secretory granule lumen / protein phosphatase binding / ubiquitin-dependent protein catabolic process / ficolin-1-rich granule lumen / proteasome-mediated ubiquitin-dependent protein catabolic process / regulation of apoptotic process / Attachment and Entry / protein ubiquitination / protein domain specific binding / DNA repair / ubiquitin protein ligase binding / lipid binding / DNA damage response / Neutrophil degranulation / endoplasmic reticulum membrane / perinuclear region of cytoplasm
Similarity search - Function
AAA ATPase, CDC48 family / CDC48, N-terminal subdomain / Cell division protein 48 (CDC48), N-terminal domain / Cell division protein 48 (CDC48) N-terminal domain / CDC48, domain 2 / Cell division protein 48 (CDC48) domain 2 / Cell division protein 48 (CDC48), domain 2 / : / CDC48 domain 2-like superfamily / Aspartate decarboxylase-like domain superfamily ...AAA ATPase, CDC48 family / CDC48, N-terminal subdomain / Cell division protein 48 (CDC48), N-terminal domain / Cell division protein 48 (CDC48) N-terminal domain / CDC48, domain 2 / Cell division protein 48 (CDC48) domain 2 / Cell division protein 48 (CDC48), domain 2 / : / CDC48 domain 2-like superfamily / Aspartate decarboxylase-like domain superfamily / AAA ATPase, AAA+ lid domain / AAA+ lid domain / ATPase, AAA-type, conserved site / AAA-protein family signature. / ATPase family associated with various cellular activities (AAA) / ATPase, AAA-type, core / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
ADENOSINE-5'-DIPHOSPHATE / Transitional endoplasmic reticulum ATPase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.13 Å
AuthorsTamayo-Jaramillo, D. / Shen, P.S.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35 GM133772 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R01 CA293084 United States
CitationJournal: Adv Sci (Weinh) / Year: 2026
Title: Development and Structural Characterization of UTE-156, a Covalent Inhibitor of the VCP/p97 AAA+ ATPase.
Authors: Daniela Tamayo-Jaramillo / Subramanya Hegde / Xuan Jia / Kimberly Coffman / Hariprasad Vankayalapati / David Bearss / Kevin B Jones / Alex W Stark / Peter S Shen /
Abstract: 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. ...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.
History
DepositionFeb 2, 2026Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 18, 2026Provider: repository / Type: Initial release
Revision 1.0Mar 18, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Mar 18, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 18, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 18, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Mar 18, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1May 13, 2026Group: Data collection / Database references / Category: citation / em_admin / Item: _citation.journal_volume / _em_admin.last_update
Revision 1.1May 13, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / Category: citation / em_admin / Data content type: EM metadata / EM metadata / Item: _citation.journal_volume / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Transitional endoplasmic reticulum ATPase
B: Transitional endoplasmic reticulum ATPase
C: Transitional endoplasmic reticulum ATPase
D: Transitional endoplasmic reticulum ATPase
E: Transitional endoplasmic reticulum ATPase
F: Transitional endoplasmic reticulum ATPase
G: Transitional endoplasmic reticulum ATPase
H: Transitional endoplasmic reticulum ATPase
I: Transitional endoplasmic reticulum ATPase
J: Transitional endoplasmic reticulum ATPase
K: Transitional endoplasmic reticulum ATPase
L: Transitional endoplasmic reticulum ATPase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)1,084,07860
Polymers1,073,24212
Non-polymers10,83648
Water1,08160
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein
Transitional endoplasmic reticulum ATPase / TER ATPase / 15S Mg(2+)-ATPase p97 subunit / Valosin-containing protein / VCP


Mass: 89436.820 Da / Num. of mol.: 12
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: VCP / Production host: Escherichia coli (E. coli) / References: UniProt: P55072, vesicle-fusing ATPase
#2: Chemical...
ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 24 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: ADP, energy-carrying molecule*YM
#3: Chemical...
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 24 / Source method: obtained synthetically / Formula: Mg
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 60 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Human VCP/p97 bound to ADP (DMSO control) / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 1.084 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.4 / Details: 20 mM HEPES-KOH pH 7.4, 100 mM KOAc, 10mM MgCl2
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 165000 X / Nominal defocus max: 2200 nm / Nominal defocus min: 400 nm / Cs: 2.7 mm
Image recordingElectron dose: 50.64 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
4cryoSPARCCTF correction
10cryoSPARCinitial Euler assignment
11cryoSPARCfinal Euler assignment
12cryoSPARCclassification
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.13 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 79312 / Symmetry type: POINT

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