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- PDB-9fit: Structure-guided discovery of selective USP7 inhibitors with in v... -

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Basic information

Entry
Database: PDB / ID: 9fit
TitleStructure-guided discovery of selective USP7 inhibitors with in vivo activity
ComponentsUbiquitin carboxyl-terminal hydrolase 7
KeywordsHYDROLASE / HAUSP / USP7 / SBDD / HYDROLASE-HYDROLASE INHIBITOR COMPLEX
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 / negative regulation of gene expression via chromosomal CpG island methylation ...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 / negative regulation of gene expression via chromosomal CpG island methylation / negative regulation of NF-kappaB transcription factor activity / protein deubiquitination / negative regulation of gluconeogenesis / transcription-coupled nucleotide-excision repair / negative regulation of TORC1 signaling / negative regulation of proteasomal ubiquitin-dependent protein catabolic process / Regulation of PTEN localization / Synthesis of active ubiquitin: roles of E1 and E2 enzymes / regulation of signal transduction by p53 class mediator / regulation of circadian rhythm / regulation of protein stability / PML body / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / p53 binding / rhythmic process / Regulation of TP53 Degradation / chromosome / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / protein stabilization / Ub-specific processing proteases / protein ubiquitination / nuclear body / cysteine-type endopeptidase activity / protein-containing complex / proteolysis / nucleoplasm / nucleus / cytosol
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. / Papain-like cysteine peptidase superfamily
Similarity search - Domain/homology
: / Ubiquitin carboxyl-terminal hydrolase 7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsBaker, L.M. / Murray, J. / Hubbard, R.E. / Whitehead, N.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Structure-Guided Discovery of Selective USP7 Inhibitors with In Vivo Activity.
Authors: Vasas, A. / Ivanschitz, L. / Molnar, B. / Kiss, A. / Baker, L. / Fiumana, A. / Macias, A. / Murray, J.B. / Sanders, E. / Whitehead, N. / Hubbard, R.E. / Saunier, C. / Monceau, E. / Girard, A. ...Authors: Vasas, A. / Ivanschitz, L. / Molnar, B. / Kiss, A. / Baker, L. / Fiumana, A. / Macias, A. / Murray, J.B. / Sanders, E. / Whitehead, N. / Hubbard, R.E. / Saunier, C. / Monceau, E. / Girard, A.M. / Rousseau, M. / Chanrion, M. / Demarles, D. / Geneste, O. / Weber, C. / Lewkowicz, E. / Kotschy, A.
History
DepositionMay 29, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 6, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 27, 2024Group: 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

Downloads & links

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Assembly

Deposited unit
A: Ubiquitin carboxyl-terminal hydrolase 7
B: Ubiquitin carboxyl-terminal hydrolase 7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)83,3924
Polymers82,1452
Non-polymers1,2482
Water1,56787
1
A: Ubiquitin carboxyl-terminal hydrolase 7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,6962
Polymers41,0721
Non-polymers6241
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Ubiquitin carboxyl-terminal hydrolase 7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,6962
Polymers41,0721
Non-polymers6241
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)74.764, 67.688, 77.513
Angle α, β, γ (deg.)90, 90.543, 90
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21A

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: THR / Beg label comp-ID: THR / End auth comp-ID: ALA / End label comp-ID: ALA / Auth asym-ID: A / Label asym-ID: A / Auth seq-ID: 211 - 552 / Label seq-ID: 6 - 347

Dom-ID
1
2

NCS ensembles : (Details: Local NCS retraints between domains: 1 2)

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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: 41072.379 Da / Num. of mol.: 2 / Mutation: F409A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: USP7, HAUSP / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): pLysS / References: UniProt: Q93009, ubiquitinyl hydrolase 1
#2: Chemical ChemComp-A1ICT / 7-methyl-3-[[4-oxidanyl-1-[(3~{R},4~{R})-3-phenyl-1-[(5-pyrimidin-5-ylthiophen-2-yl)methyl]piperidin-4-yl]carbonyl-piperidin-4-yl]methyl]pyrrolo[2,3-d]pyrimidin-4-one


Mass: 623.768 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H37N7O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 87 / 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: 2.39 Å3/Da / Density % sol: 48.48 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / Details: 23% peg 3350, 0.6 M sodium formate, 10 mM DTT

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: BRUKER X8 PROTEUM / Wavelength: 1.542 Å
DetectorType: Bruker PHOTON II / Detector: PIXEL / Date: Aug 11, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.542 Å / Relative weight: 1
ReflectionResolution: 2.2→21.66 Å / Num. obs: 37692 / % possible obs: 95.4 % / Redundancy: 3.81 % / Rmerge(I) obs: 0.1689 / Net I/σ(I): 5.91
Reflection shellResolution: 2.2→2.3 Å / Redundancy: 2.17 % / Rmerge(I) obs: 0.5394 / Mean I/σ(I) obs: 1.55 / Num. unique obs: 4455 / % possible all: 91

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Processing

Software
NameVersionClassification
REFMAC5.8.0425refinement
SAINTdata reduction
SADABSdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.7→21.66 Å / Cor.coef. Fo:Fc: 0.846 / Cor.coef. Fo:Fc free: 0.761 / SU B: 18.973 / SU ML: 0.373 / Cross valid method: FREE R-VALUE / ESU R Free: 0.102
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.3281 1042 5.028 %
Rwork0.273 19681 -
all0.276 --
obs-20723 96.719 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 30.517 Å2
Baniso -1Baniso -2Baniso -3
1--15.773 Å2-0 Å2-16.247 Å2
2--13.202 Å20 Å2
3---2.571 Å2
Refinement stepCycle: LAST / Resolution: 2.7→21.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5273 0 90 87 5450
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0125479
X-RAY DIFFRACTIONr_bond_other_d0.0010.0165142
X-RAY DIFFRACTIONr_angle_refined_deg1.881.8767396
X-RAY DIFFRACTIONr_angle_other_deg0.6361.80611890
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.2875646
X-RAY DIFFRACTIONr_dihedral_angle_2_deg10.983526
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.8310987
X-RAY DIFFRACTIONr_dihedral_angle_6_deg16.26510271
X-RAY DIFFRACTIONr_chiral_restr0.0840.2784
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.026313
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021227
X-RAY DIFFRACTIONr_nbd_refined0.2360.21315
X-RAY DIFFRACTIONr_symmetry_nbd_other0.2190.25475
X-RAY DIFFRACTIONr_nbtor_refined0.1970.22597
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0890.23188
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2360.2194
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.2360.26
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.4850.218
X-RAY DIFFRACTIONr_nbd_other0.4060.256
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.0350.21
X-RAY DIFFRACTIONr_mcbond_it3.0942.9432605
X-RAY DIFFRACTIONr_mcbond_other3.0922.9432605
X-RAY DIFFRACTIONr_mcangle_it5.0695.2653244
X-RAY DIFFRACTIONr_mcangle_other5.0695.2673245
X-RAY DIFFRACTIONr_scbond_it3.013.2182874
X-RAY DIFFRACTIONr_scbond_other3.0113.2212875
X-RAY DIFFRACTIONr_scangle_it5.0265.784152
X-RAY DIFFRACTIONr_scangle_other5.0265.7824153
X-RAY DIFFRACTIONr_lrange_it9.1834.79122746
X-RAY DIFFRACTIONr_lrange_other9.17934.82422720
X-RAY DIFFRACTIONr_ncsr_local_group_10.2010.059749
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)Weight position
11AX-RAY DIFFRACTIONLocal ncs0.200510.05005
12AX-RAY DIFFRACTIONLocal ncs0.200510.05005
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
2.7-2.7690.48710.40214120.40515500.8170.88595.67740.39
2.769-2.8430.434740.35713570.36115030.8730.92395.20960.348
2.843-2.9240.328750.34813230.34714610.9430.93295.68790.336
2.924-3.0120.371760.32212950.32414270.9230.94496.07570.305
3.012-3.1080.387590.31812890.32114040.9290.94796.01140.301
3.108-3.2140.397660.31512090.31913330.9030.93795.64890.293
3.214-3.3330.371650.32311680.32513040.8960.92594.55520.296
3.333-3.4650.327620.31111170.31212380.9250.93995.23420.28
3.465-3.6140.314670.28710950.28812170.9270.94995.48070.254
3.614-3.7840.32480.27910240.28111480.9320.95293.37980.251
3.784-3.9810.305640.24610120.2511090.9440.96497.02430.219
3.981-4.2120.268360.1939910.19510460.9670.97998.18350.163
4.212-4.4880.24490.1879100.199720.9660.9898.66260.164
4.488-4.8280.362420.2028900.2089340.9570.9899.78590.174
4.828-5.2580.281400.2048110.2078520.9540.98199.88260.175
5.258-5.8280.192370.2327400.237790.9860.97599.74330.203
5.828-6.6370.334400.2476650.2527050.9270.9671000.217
6.637-7.9140.268330.215720.2136050.960.9771000.197
7.914-10.4070.237220.1994670.2014890.9770.9821000.196
10.407-20.0020.271160.2523340.2533500.9740.9721000.252

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