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- EMDB-42625: Human p97/VCP R155H mutant structure with a triazole inhibitor (N... -

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Entry
Database: EMDB / ID: EMD-42625
TitleHuman p97/VCP R155H mutant structure with a triazole inhibitor (NSC804515)
Map dataSharpened map.
Sample
  • Complex: p97/VCP AAA+ ATPase R155H mutant/NSC804515
    • Protein or peptide: Transitional endoplasmic reticulum ATPase
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: N-[3-(2,5-difluoro-4-{[(4M)-5-(hexylsulfanyl)-4-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]methoxy}phenyl)prop-2-yn-1-yl]propanamide
KeywordsAAA+ ATPase / p97 / VCP / triazole / allosteric inhibition / MOTOR PROTEIN / MOTOR PROTEIN-INHIBITOR complex
Function / homology
Function and homology information


flavin adenine dinucleotide catabolic process / positive regulation of Lys63-specific deubiquitinase activity / positive regulation of oxidative phosphorylation / VCP-NSFL1C complex / endosome to lysosome transport via multivesicular body sorting pathway / endoplasmic reticulum stress-induced pre-emptive quality control / positive regulation of protein K63-linked deubiquitination / cellular response to arsenite ion / Derlin-1 retrotranslocation complex / BAT3 complex binding ...flavin adenine dinucleotide catabolic process / positive regulation of Lys63-specific deubiquitinase activity / positive regulation of oxidative phosphorylation / VCP-NSFL1C complex / endosome to lysosome transport via multivesicular body sorting pathway / endoplasmic reticulum stress-induced pre-emptive quality control / positive regulation of protein K63-linked deubiquitination / cellular response to arsenite ion / Derlin-1 retrotranslocation complex / BAT3 complex binding / cytoplasm protein quality control / protein-DNA covalent cross-linking repair / deubiquitinase activator activity / mitotic spindle disassembly / ubiquitin-modified protein reader activity / positive regulation of mitochondrial membrane potential / aggresome assembly / regulation of protein localization to chromatin / NADH metabolic process / VCP-NPL4-UFD1 AAA ATPase complex / vesicle-fusing ATPase / cellular response to misfolded protein / negative regulation of protein localization to chromatin / retrograde protein transport, ER to cytosol / positive regulation of ATP biosynthetic process / K48-linked polyubiquitin modification-dependent protein binding / regulation of aerobic respiration / stress granule disassembly / regulation of synapse organization / ATPase complex / ubiquitin-specific protease binding / MHC class I protein binding / ubiquitin-like protein ligase binding / RHOH GTPase cycle / autophagosome maturation / polyubiquitin modification-dependent protein binding / HSF1 activation / negative regulation of hippo signaling / endoplasmic reticulum to Golgi vesicle-mediated transport / proteasomal protein catabolic process / ATP metabolic process / translesion synthesis / interstrand cross-link repair / Protein methylation / endoplasmic reticulum unfolded protein response / negative regulation of smoothened signaling pathway / ERAD pathway / Attachment and Entry / viral genome replication / proteasome complex / lipid droplet / Josephin domain DUBs / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / Hh mutants are degraded by ERAD / macroautophagy / Hedgehog ligand biogenesis / Defective CFTR causes cystic fibrosis / establishment of protein localization / Translesion Synthesis by POLH / positive regulation of protein-containing complex assembly / positive regulation of non-canonical NF-kappaB signal transduction / : / ABC-family proteins mediated transport / ADP binding / autophagy / Aggrephagy / positive regulation of protein catabolic process / cytoplasmic stress granule / azurophil granule lumen / KEAP1-NFE2L2 pathway / positive regulation of canonical Wnt signaling pathway / Ovarian tumor domain proteases / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / double-strand break repair / E3 ubiquitin ligases ubiquitinate target proteins / site of double-strand break / Neddylation / cellular response to heat / ubiquitin-dependent protein catabolic process / protein phosphatase binding / secretory granule lumen / regulation of apoptotic process / proteasome-mediated ubiquitin-dependent protein catabolic process / ficolin-1-rich granule lumen / Attachment and Entry / protein ubiquitination / protein domain specific binding / intracellular membrane-bounded organelle / DNA repair / lipid binding / ubiquitin protein ligase binding / DNA damage response / Neutrophil degranulation / endoplasmic reticulum membrane / perinuclear region of cytoplasm / glutamatergic synapse / endoplasmic reticulum / ATP hydrolysis activity / protein-containing complex / RNA binding
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
Transitional endoplasmic reticulum ATPase
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.22 Å
AuthorsNandi P / DeVore K / Chiu P-L
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
CitationJournal: Commun Chem / Year: 2024
Title: Mechanism of allosteric inhibition of human p97/VCP ATPase and its disease mutant by triazole inhibitors.
Authors: Purbasha Nandi / Kira DeVore / Feng Wang / Shan Li / Joel D Walker / Thanh Tung Truong / Matthew G LaPorte / Peter Wipf / Heidi Schlager / John McCleerey / William Paquette / Rod Carlo A ...Authors: Purbasha Nandi / Kira DeVore / Feng Wang / Shan Li / Joel D Walker / Thanh Tung Truong / Matthew G LaPorte / Peter Wipf / Heidi Schlager / John McCleerey / William Paquette / Rod Carlo A Columbres / Taiping Gan / Yu-Ping Poh / Petra Fromme / Andrew J Flint / Mark Wolf / Donna M Huryn / Tsui-Fen Chou / Po-Lin Chiu /
Abstract: Human p97 ATPase is crucial in various cellular processes, making it a target for inhibitors to treat cancers, neurological, and infectious diseases. Triazole allosteric p97 inhibitors have been ...Human p97 ATPase is crucial in various cellular processes, making it a target for inhibitors to treat cancers, neurological, and infectious diseases. Triazole allosteric p97 inhibitors have been demonstrated to match the efficacy of CB-5083, an ATP-competitive inhibitor, in cellular models. However, the mechanism is not well understood. This study systematically investigates the structures of new triazole inhibitors bound to  both wild-type and disease mutant forms of p97 and measures their effects on function. These inhibitors bind at the interface of the D1 and D2 domains of each p97 subunit, shifting surrounding helices and altering the loop structures near the C-terminal α2 G helix to modulate domain-domain communications. A key structural moiety of the inhibitor affects the rotameric conformations of interacting side chains, indirectly modulating the N-terminal domain conformation in p97 R155H mutant. The differential effects of inhibitor binding to wild-type and mutant p97 provide insights into drug design with enhanced specificity, particularly for oncology applications.
History
DepositionNov 3, 2023-
Header (metadata) releaseAug 21, 2024-
Map releaseAug 21, 2024-
UpdateAug 21, 2024-
Current statusAug 21, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_42625.png

Downloads & links

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Map

FileDownload / File: emd_42625.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.04 Å/pix.
x 300 pix.
= 312. Å		1.04 Å/pix.
x 300 pix.
= 312. Å		1.04 Å/pix.
x 300 pix.
= 312. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.04 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.85
Minimum - Maximum-9.596145 - 16.769462999999998
Average (Standard dev.)0.0027780407 (±0.691713)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 312.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half map 1.

Fileemd_42625_half_map_1.map
AnnotationHalf map 1.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 2.

Fileemd_42625_half_map_2.map
AnnotationHalf map 2.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : p97/VCP AAA+ ATPase R155H mutant/NSC804515

EntireName: p97/VCP AAA+ ATPase R155H mutant/NSC804515
Components
  • Complex: p97/VCP AAA+ ATPase R155H mutant/NSC804515
    • Protein or peptide: Transitional endoplasmic reticulum ATPase
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: N-[3-(2,5-difluoro-4-{[(4M)-5-(hexylsulfanyl)-4-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]methoxy}phenyl)prop-2-yn-1-yl]propanamide

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Supramolecule #1: p97/VCP AAA+ ATPase R155H mutant/NSC804515

SupramoleculeName: p97/VCP AAA+ ATPase R155H mutant/NSC804515 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Details: p97/VCP AAA+ ATPase R155H mutant bound with the triazole NSC804515.
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 536 KDa

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Macromolecule #1: Transitional endoplasmic reticulum ATPase

MacromoleculeName: Transitional endoplasmic reticulum ATPase / type: protein_or_peptide / ID: 1 / Number of copies: 6 / Enantiomer: LEVO / EC number: vesicle-fusing ATPase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 89.417773 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MASGADSKGD DLSTAILKQK NRPNRLIVDE AINEDNSVVS LSQPKMDELQ LFRGDTVLLK GKKRREAVCI VLSDDTCSDE KIRMNRVVR NNLRVRLGDV ISIQPCPDVK YGKRIHVLPI DDTVEGITGN LFEVYLKPYF LEAYRPIRKG DIFLVHGGMR A VEFKVVET ...String:
MASGADSKGD DLSTAILKQK NRPNRLIVDE AINEDNSVVS LSQPKMDELQ LFRGDTVLLK GKKRREAVCI VLSDDTCSDE KIRMNRVVR NNLRVRLGDV ISIQPCPDVK YGKRIHVLPI DDTVEGITGN LFEVYLKPYF LEAYRPIRKG DIFLVHGGMR A VEFKVVET DPSPYCIVAP DTVIHCEGEP IKREDEEESL NEVGYDDIGG CRKQLAQIKE MVELPLRHPA LFKAIGVKPP RG ILLYGPP GTGKTLIARA VANETGAFFF LINGPEIMSK LAGESESNLR KAFEEAEKNA PAIIFIDELD AIAPKREKTH GEV ERRIVS QLLTLMDGLK QRAHVIVMAA TNRPNSIDPA LRRFGRFDRE VDIGIPDATG RLEILQIHTK NMKLADDVDL EQVA NETHG HVGADLAALC SEAALQAIRK KMDLIDLEDE TIDAEVMNSL AVTMDDFRWA LSQSNPSALR ETVVEVPQVT WEDIG GLED VKRELQELVQ YPVEHPDKFL KFGMTPSKGV LFYGPPGCGK TLLAKAIANE CQANFISIKG PELLTMWFGE SEANVR EIF DKARQAAPCV LFFDELDSIA KARGGNIGDG GGAADRVINQ ILTEMDGMST KKNVFIIGAT NRPDIIDPAI LRPGRLD QL IYIPLPDEKS RVAILKANLR KSPVAKDVDL EFLAKMTNGF SGADLTEICQ RACKLAIRES IESEIRRERE RQTNPSAM E VEEDDPVPEI RRDHFEEAMR FARRSVSDND IRKYEMFAQT LQQSRGFGSF RFPSGNQGGA GPSQGSGGGT GGSVYTEDN DDDLYG

UniProtKB: Transitional endoplasmic reticulum ATPase

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Macromolecule #2: ADENOSINE-5'-DIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-DIPHOSPHATE / type: ligand / ID: 2 / Number of copies: 12 / Formula: ADP
Molecular weightTheoretical: 427.201 Da
Chemical component information

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

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Macromolecule #3: N-[3-(2,5-difluoro-4-{[(4M)-5-(hexylsulfanyl)-4-(pyridin-3-yl)-4H...

MacromoleculeName: N-[3-(2,5-difluoro-4-{[(4M)-5-(hexylsulfanyl)-4-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]methoxy}phenyl)prop-2-yn-1-yl]propanamide
type: ligand / ID: 3 / Number of copies: 6 / Formula: XNU
Molecular weightTheoretical: 513.603 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
Component:
ConcentrationFormulaName
20.0 mMHEPESHEPES
150.0 mMKClPotassium chloride
1.0 mMMgCl2Magnesium chloride
1.0 mMADPAdenosine diphosphate
GridModel: C-flat-2/1 / Material: COPPER / Mesh: 400 / Support film - Material: CARBON / Support film - topology: HOLEY ARRAY / Support film - Film thickness: 30 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 15 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 298 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 47.84 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 48077
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C6 (6 fold cyclic) / Algorithm: BACK PROJECTION / Resolution.type: BY AUTHOR / Resolution: 3.22 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cisTEM (ver. 1.0.0) / Number images used: 27998
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1)
Final 3D classificationSoftware - Name: RELION (ver. 3.1)

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Atomic model buiding 1

Initial modelPDB ID:

5ftn


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-8uvo:
Human p97/VCP R155H mutant structure with a triazole inhibitor (NSC804515)

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