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- PDB-9yp6: Structure of human VCP/p97 hexamer bound to ADP and UTE-156 -

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Basic information

Entry
Database: PDB / ID: 9yp6
TitleStructure of human VCP/p97 hexamer bound to ADP and UTE-156
ComponentsTransitional endoplasmic reticulum ATPase
KeywordsCHAPERONE / inhibitor / UTE-156 / VCP / p97 / covalent / hexamer
Function / homology
Function and homology information


flavin adenine dinucleotide catabolic process / VCP-NSFL1C complex / cytoplasmic ubiquitin ligase 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 / protein-DNA covalent cross-linking repair / Derlin-1 retrotranslocation complex / positive regulation of protein K63-linked deubiquitination ...flavin adenine dinucleotide catabolic process / VCP-NSFL1C complex / cytoplasmic ubiquitin ligase 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 / protein-DNA covalent cross-linking repair / Derlin-1 retrotranslocation complex / positive regulation of protein K63-linked deubiquitination / deubiquitinase activator activity / cytoplasm protein quality control / positive regulation of oxidative phosphorylation / aggresome assembly / ubiquitin-modified protein reader activity / regulation of protein localization to chromatin / mitotic spindle disassembly / cellular response to misfolded protein / VCP-NPL4-UFD1 AAA ATPase complex / ciliary transition zone / 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 / positive regulation of ATP biosynthetic process / ubiquitin-like protein ligase binding / MHC class I protein binding / RHOH GTPase cycle / polyubiquitin modification-dependent protein binding / autophagosome maturation / endoplasmic reticulum to Golgi vesicle-mediated transport / negative regulation of hippo signaling / HSF1 activation / interstrand cross-link repair / ATP metabolic process / translesion synthesis / proteasomal protein catabolic process / Attachment and Entry / endoplasmic reticulum unfolded protein response / Protein methylation / ERAD pathway / negative regulation of protein localization to chromatin / ciliary tip / lipid droplet / proteasome complex / viral genome replication / Josephin domain DUBs / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / macroautophagy / negative regulation of smoothened signaling pathway / establishment of protein localization / Hh mutants are degraded by ERAD / positive regulation of protein-containing complex assembly / Hedgehog ligand biogenesis / Defective CFTR causes cystic fibrosis / positive regulation of non-canonical NF-kappaB signal transduction / Translesion Synthesis by POLH / ADP binding / ABC-family proteins mediated transport / autophagy / cytoplasmic stress granule / Aggrephagy / positive regulation of protein catabolic process / azurophil granule lumen / Ovarian tumor domain proteases / KEAP1-NFE2L2 pathway / positive regulation of canonical Wnt signaling pathway / double-strand break repair / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / E3 ubiquitin ligases ubiquitinate target proteins / cellular response to heat / site of double-strand break / Neddylation / secretory granule lumen / protein phosphatase binding / regulation of apoptotic process / intracellular membrane-bounded organelle / ficolin-1-rich granule lumen / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / Attachment and Entry / ciliary basal body / protein ubiquitination / protein domain specific binding / DNA repair / DNA damage response / ubiquitin protein ligase binding / Neutrophil degranulation / lipid binding / endoplasmic reticulum membrane / perinuclear region of cytoplasm / glutamatergic synapse / endoplasmic reticulum / ATP hydrolysis activity
Similarity search - Function
AAA ATPase, CDC48 family / Cell division protein 48 (CDC48), N-terminal domain / : / CDC48, N-terminal subdomain / 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 / Cell division protein 48 (CDC48), N-terminal domain / : / CDC48, N-terminal subdomain / 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: 2.8 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
DepositionOct 13, 2025Deposition 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: Additional map / Part number: 1 / Data content type: Additional map / 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)541,57518
Polymers536,6216
Non-polymers4,95412
Water21612
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.: 6
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.: 6 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
#3: Chemical
ChemComp-A1CYL / N-(3-{[(6P)-2-(methanesulfonyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl]amino}phenyl)prop-2-enamide


Mass: 398.439 Da / Num. of mol.: 6 / Source method: isolated from a natural source / Formula: C18H18N6O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 12 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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 hexamer bound to ADP and UTE-156 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.544 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.4 / Details: 25 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: 91 % / 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: 105000 X / Nominal defocus max: 1500 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm
Image recordingAverage exposure time: 2.5 sec. / Electron dose: 52.015 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.6.2particle selection
2SerialEMimage acquisition
4cryoSPARC4.6.2CTF correction
10cryoSPARC4.6.2initial Euler assignment
11cryoSPARC4.6.2final Euler assignment
13cryoSPARC4.6.23D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 204722 / Symmetry type: POINT

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