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- PDB-9iml: Sertraline enhances the deubiquitinase activity of USP7 by bindin... -

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Basic information

Entry
Database: PDB / ID: 9iml
TitleSertraline enhances the deubiquitinase activity of USP7 by binding to its switching loop region
Components
  • Ubiquitin
  • Ubiquitin carboxyl-terminal hydrolase 7
KeywordsHYDROLASE / ubiquitin specific protease
Function / homology
Function and homology information


regulation of telomere capping / regulation of establishment of protein localization to telomere / monoubiquitinated protein deubiquitination / regulation of retrograde transport, endosome to Golgi / deubiquitinase activity / DNA alkylation repair / regulation of DNA-binding transcription factor activity / K48-linked deubiquitinase activity / symbiont-mediated disruption of host cell PML body / Formation of the ternary complex, and subsequently, the 43S complex ...regulation of telomere capping / regulation of establishment of protein localization to telomere / monoubiquitinated protein deubiquitination / regulation of retrograde transport, endosome to Golgi / deubiquitinase activity / DNA alkylation repair / regulation of DNA-binding transcription factor activity / K48-linked deubiquitinase activity / symbiont-mediated disruption of host cell PML body / Formation of the ternary complex, and subsequently, the 43S complex / negative regulation of NF-kappaB transcription factor activity / negative regulation of gene expression via chromosomal CpG island methylation / Ribosomal scanning and start codon recognition / Translation initiation complex formation / SARS-CoV-1 modulates host translation machinery / Peptide chain elongation / Selenocysteine synthesis / Formation of a pool of free 40S subunits / Eukaryotic Translation Termination / Response of EIF2AK4 (GCN2) to amino acid deficiency / SRP-dependent cotranslational protein targeting to membrane / protein deubiquitination / Viral mRNA Translation / Maturation of protein E / Maturation of protein E / Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) / GTP hydrolysis and joining of the 60S ribosomal subunit / ER Quality Control Compartment (ERQC) / Myoclonic epilepsy of Lafora / FLT3 signaling by CBL mutants / negative regulation of gluconeogenesis / Prevention of phagosomal-lysosomal fusion / L13a-mediated translational silencing of Ceruloplasmin expression / IRAK2 mediated activation of TAK1 complex / Alpha-protein kinase 1 signaling pathway / Glycogen synthesis / IRAK1 recruits IKK complex / IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation / Membrane binding and targetting of GAG proteins / Endosomal Sorting Complex Required For Transport (ESCRT) / Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7 / Negative regulation of FLT3 / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / Regulation of TBK1, IKKε-mediated activation of IRF3, IRF7 upon TLR3 ligation / Constitutive Signaling by NOTCH1 HD Domain Mutants / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / NOTCH2 Activation and Transmission of Signal to the Nucleus / Major pathway of rRNA processing in the nucleolus and cytosol / TICAM1,TRAF6-dependent induction of TAK1 complex / TICAM1-dependent activation of IRF3/IRF7 / APC/C:Cdc20 mediated degradation of Cyclin B / Regulation of FZD by ubiquitination / Downregulation of ERBB4 signaling / p75NTR recruits signalling complexes / APC-Cdc20 mediated degradation of Nek2A / InlA-mediated entry of Listeria monocytogenes into host cells / Regulation of pyruvate metabolism / transcription-coupled nucleotide-excision repair / TRAF6-mediated induction of TAK1 complex within TLR4 complex / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / Regulation of innate immune responses to cytosolic DNA / NF-kB is activated and signals survival / Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) / Downregulation of ERBB2:ERBB3 signaling / NRIF signals cell death from the nucleus / Pexophagy / VLDLR internalisation and degradation / Regulation of PTEN localization / Activated NOTCH1 Transmits Signal to the Nucleus / Regulation of BACH1 activity / MAP3K8 (TPL2)-dependent MAPK1/3 activation / Translesion synthesis by REV1 / Synthesis of active ubiquitin: roles of E1 and E2 enzymes / InlB-mediated entry of Listeria monocytogenes into host cell / Translesion synthesis by POLK / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / Downregulation of TGF-beta receptor signaling / Josephin domain DUBs / TICAM1, RIP1-mediated IKK complex recruitment / negative regulation of TORC1 signaling / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / Translesion synthesis by POLI / Gap-filling DNA repair synthesis and ligation in GG-NER / IKK complex recruitment mediated by RIP1 / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / Regulation of activated PAK-2p34 by proteasome mediated degradation / negative regulation of proteasomal ubiquitin-dependent protein catabolic process / TNFR1-induced NF-kappa-B signaling pathway / PINK1-PRKN Mediated Mitophagy / cytosolic ribosome / TCF dependent signaling in response to WNT / Autodegradation of Cdh1 by Cdh1:APC/C / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / APC/C:Cdc20 mediated degradation of Securin / activated TAK1 mediates p38 MAPK activation / Regulation of NF-kappa B signaling / Asymmetric localization of PCP proteins / Ubiquitin-dependent degradation of Cyclin D / Regulation of signaling by CBL / NIK-->noncanonical NF-kB signaling
Similarity search - Function
Ubiquitin carboxyl-terminal hydrolase 7, ICP0-binding domain / ICP0-binding domain of Ubiquitin-specific protease 7 / Ubiquitin carboxyl-terminal hydrolase, C-terminal / Ubiquitin-specific protease C-terminal / MATH domain / : / MATH/TRAF domain / MATH/TRAF domain profile. / meprin and TRAF homology / TRAF-like ...Ubiquitin carboxyl-terminal hydrolase 7, ICP0-binding domain / ICP0-binding domain of Ubiquitin-specific protease 7 / Ubiquitin carboxyl-terminal hydrolase, C-terminal / Ubiquitin-specific protease C-terminal / MATH domain / : / MATH/TRAF domain / MATH/TRAF domain profile. / meprin and TRAF homology / TRAF-like / Ubiquitin specific protease (USP) domain signature 2. / Ubiquitin specific protease (USP) domain signature 1. / Ubiquitin specific protease, conserved site / Peptidase C19, ubiquitin carboxyl-terminal hydrolase / Ubiquitin carboxyl-terminal hydrolase / Ubiquitin specific protease domain / Ubiquitin specific protease (USP) domain profile. / S27a-like superfamily / Ribosomal protein S27a / Ribosomal protein S27a / Ribosomal protein S27a / Papain-like cysteine peptidase superfamily / : / Ubiquitin domain / Ubiquitin domain signature. / Ubiquitin conserved site / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Zinc-binding ribosomal protein / Ubiquitin-like domain superfamily
Similarity search - Domain/homology
Chem-XB7 / Ubiquitin-ribosomal protein eS31 fusion protein / Ubiquitin carboxyl-terminal hydrolase 7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.78 Å
AuthorsShi, L. / Xu, Z. / Chen, X. / Xiong, B. / Zhang, N.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32171220 China
CitationJournal: J.Med.Chem. / Year: 2025
Title: Sertraline and Astemizole Enhance the Deubiquitinase Activity of USP7 by Binding to Its Switching Loop Region.
Authors: Shi, L. / Xu, Z. / Chen, X. / Meng, Q. / Zhou, H. / Xiong, B. / Zhang, N.
History
DepositionJul 3, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Mar 12, 2025Provider: repository / Type: Initial release
Revision 1.1Mar 26, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Ubiquitin carboxyl-terminal hydrolase 7
B: Ubiquitin
C: Ubiquitin carboxyl-terminal hydrolase 7
D: Ubiquitin
E: Ubiquitin carboxyl-terminal hydrolase 7
F: Ubiquitin
G: Ubiquitin carboxyl-terminal hydrolase 7
H: Ubiquitin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)198,5559
Polymers198,0968
Non-polymers4591
Water73941
1
A: Ubiquitin carboxyl-terminal hydrolase 7
B: Ubiquitin


Theoretical massNumber of molelcules
Total (without water)49,5242
Polymers49,5242
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3290 Å2
ΔGint-5 kcal/mol
Surface area15900 Å2
MethodPISA
2
C: Ubiquitin carboxyl-terminal hydrolase 7
D: Ubiquitin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,9833
Polymers49,5242
Non-polymers4591
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3080 Å2
ΔGint-7 kcal/mol
Surface area15200 Å2
MethodPISA
3
E: Ubiquitin carboxyl-terminal hydrolase 7
F: Ubiquitin


Theoretical massNumber of molelcules
Total (without water)49,5242
Polymers49,5242
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3210 Å2
ΔGint-4 kcal/mol
Surface area16040 Å2
MethodPISA
4
G: Ubiquitin carboxyl-terminal hydrolase 7
H: Ubiquitin


Theoretical massNumber of molelcules
Total (without water)49,5242
Polymers49,5242
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3150 Å2
ΔGint-7 kcal/mol
Surface area15570 Å2
MethodPISA
Unit cell
Length a, b, c (Å)101.570, 84.970, 106.990
Angle α, β, γ (deg.)90.00, 90.11, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein
Ubiquitin carboxyl-terminal hydrolase 7 / Deubiquitinating enzyme 7 / Herpesvirus-associated ubiquitin-specific protease / Ubiquitin ...Deubiquitinating enzyme 7 / Herpesvirus-associated ubiquitin-specific protease / Ubiquitin thioesterase 7 / Ubiquitin-specific-processing protease 7


Mass: 41004.340 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: USP7, HAUSP / Production host: Escherichia coli (E. coli) / References: UniProt: Q93009, ubiquitinyl hydrolase 1
#2: Protein
Ubiquitin


Mass: 8519.778 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RPS27A, UBA80, UBCEP1 / Production host: Escherichia coli (E. coli) / References: UniProt: P62979
#3: Chemical ChemComp-XB7 / 1-[(4-fluorophenyl)methyl]-N-{1-[2-(4-methoxyphenyl)ethyl]piperidin-4-yl}-1H-benzimidazol-2-amine


Mass: 458.570 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C28H31FN4O / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 41 / 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: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.33 Å3/Da / Density % sol: 47.22 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / Details: 0.1 M Bis-tris pH 6.5, 0.2 M MgCl2, 25% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL02U1 / Wavelength: 0.9792 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jul 2, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 2.78→33.67 Å / Num. obs: 45859 / % possible obs: 99.21 % / Redundancy: 2 % / Rmerge(I) obs: 0.03838 / Net I/σ(I): 16.67
Reflection shellResolution: 2.78→2.879 Å / Rmerge(I) obs: 0.3814 / Num. unique obs: 4436

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Processing

Software
NameVersionClassification
PHENIX(1.16_3549: ???)refinement
XDSdata scaling
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1NBF

1nbf


Resolution: 2.78→33.67 Å / SU ML: 0.47 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 32.55 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2803 2277 4.98 %
Rwork0.2208 --
obs0.2239 45737 99.28 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.78→33.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11686 0 24 43 11753
LS refinement shellResolution: 2.78→2.88 Å
RfactorNum. reflection% reflection
Rfree0.2714 --
Rwork0.2328 --
obs-4436 97.09 %

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