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- PDB-5n9r: Crystal structure of USP7 in complex with a potent, selective and... -

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Basic information

Entry
Database: PDB / ID: 5n9r
TitleCrystal structure of USP7 in complex with a potent, selective and reversible small-molecule inhibitor
ComponentsUbiquitin carboxyl-terminal hydrolase 7
KeywordsHYDROLASE / USP7 / reversible / inhibitor / selective
Function / homology
Function and homology information


regulation of telomere capping / monoubiquitinated protein deubiquitination / regulation of retrograde transport, endosome to Golgi / deubiquitinase activity / DNA alkylation repair / regulation of DNA-binding transcription factor activity / negative regulation of gene expression via chromosomal CpG island methylation / K48-linked deubiquitinase activity / symbiont-mediated disruption of host cell PML body / negative regulation of NF-kappaB transcription factor activity ...regulation of telomere capping / monoubiquitinated protein deubiquitination / regulation of retrograde transport, endosome to Golgi / deubiquitinase activity / DNA alkylation repair / regulation of DNA-binding transcription factor activity / negative regulation of gene expression via chromosomal CpG island methylation / K48-linked deubiquitinase activity / symbiont-mediated disruption of host cell PML body / negative regulation of NF-kappaB transcription factor activity / protein deubiquitination / negative regulation of proteasomal ubiquitin-dependent protein catabolic process / transcription-coupled nucleotide-excision repair / negative regulation of gluconeogenesis / negative regulation of TORC1 signaling / Regulation of PTEN localization / Synthesis of active ubiquitin: roles of E1 and E2 enzymes / regulation of signal transduction by p53 class mediator / regulation of protein stability / regulation of circadian rhythm / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / PML body / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / Regulation of TP53 Degradation / rhythmic process / p53 binding / chromosome / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / nuclear body / protein stabilization / Ub-specific processing proteases / protein ubiquitination / cysteine-type endopeptidase activity / protein-containing complex / proteolysis / nucleoplasm / nucleus / cytosol
Similarity search - Function
ubp-family deubiquitinating enzyme superfamily / ubp-family deubiquitinating enzyme fold / 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 ...ubp-family deubiquitinating enzyme superfamily / ubp-family deubiquitinating enzyme fold / 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. / Single Sheet / Papain-like cysteine peptidase superfamily / Mainly Beta
Similarity search - Domain/homology
Chem-8RN / Ubiquitin carboxyl-terminal hydrolase 7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.23 Å
AuthorsHarrison, T. / Gavory, G. / O'Dowd, C. / Helm, M. / Flasz, I. / Arkoudis, E. / Dossang, A. / Hughes, C. / Cassidy, E. / McClelland, K. ...Harrison, T. / Gavory, G. / O'Dowd, C. / Helm, M. / Flasz, I. / Arkoudis, E. / Dossang, A. / Hughes, C. / Cassidy, E. / McClelland, K. / Odrzywol, E. / Page, N. / Barker, O. / Miel, H.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
United Kingdom
CitationJournal: Nat. Chem. Biol. / Year: 2018
Title: Discovery and characterization of highly potent and selective allosteric USP7 inhibitors.
Authors: Gavory, G. / O'Dowd, C.R. / Helm, M.D. / Flasz, J. / Arkoudis, E. / Dossang, A. / Hughes, C. / Cassidy, E. / McClelland, K. / Odrzywol, E. / Page, N. / Barker, O. / Miel, H. / Harrison, T.
History
DepositionFeb 27, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 6, 2017Provider: repository / Type: Initial release
Revision 1.1Dec 13, 2017Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.name
Revision 1.2Jan 24, 2018Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year
Revision 1.3Jan 17, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)84,62111
Polymers82,9982
Non-polymers1,6239
Water9,512528
1
A: Ubiquitin carboxyl-terminal hydrolase 7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,1774
Polymers41,4991
Non-polymers6793
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Ubiquitin carboxyl-terminal hydrolase 7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,4447
Polymers41,4991
Non-polymers9456
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)74.940, 66.940, 81.090
Angle α, β, γ (deg.)90.00, 105.09, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 2 molecules AB

#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: 41498.906 Da / Num. of mol.: 2
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

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Non-polymers , 5 types, 537 molecules

#2: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-8RN / 7-bromanyl-3-[[4-oxidanyl-1-[(3~{R})-3-phenylbutanoyl]piperidin-4-yl]methyl]thieno[3,2-d]pyrimidin-4-one


Mass: 490.413 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H24BrN3O3S
#5: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 528 / Source method: isolated from a natural source / Formula: H2O

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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: 2.37 Å3/Da / Density % sol: 48.18 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: PEG 4000, Tris, Li2-Sulfate.

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: ROTATING ANODE / Type: BRUKER AXS MICROSTAR / Wavelength: 1.54179 Å
DetectorType: MAR / Detector: IMAGE PLATE / Date: Jan 24, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54179 Å / Relative weight: 1
ReflectionResolution: 2.23→30 Å / Num. obs: 36846 / % possible obs: 99.6 % / Redundancy: 3.5 % / Rrim(I) all: 0.06 / Net I/σ(I): 16.4
Reflection shellResolution: 2.23→2.29 Å / Redundancy: 3.4 % / Mean I/σ(I) obs: 4.5 / Rrim(I) all: 0.31 / % possible all: 99.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
PDB_EXTRACT3.22data extraction
XDSdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1NB8

1nb8


Resolution: 2.23→20 Å / Cor.coef. Fo:Fc: 0.974 / Cor.coef. Fo:Fc free: 0.947 / SU B: 11.416 / SU ML: 0.153 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.269 / ESU R Free: 0.204 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING
RfactorNum. reflection% reflectionSelection details
Rfree0.212 1848 4.9 %RANDOM
Rwork0.148 ---
obs0.151 35975 99.2 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 63.04 Å2
Baniso -1Baniso -2Baniso -3
1-1.99 Å20 Å21.16 Å2
2---0.51 Å20 Å2
3----1.84 Å2
Refinement stepCycle: LAST / Resolution: 2.23→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5720 0 97 528 6345
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0195988
X-RAY DIFFRACTIONr_bond_other_d0.0020.025434
X-RAY DIFFRACTIONr_angle_refined_deg1.3781.9768086
X-RAY DIFFRACTIONr_angle_other_deg0.987312696
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2355716
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.43724.951309
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.118151094
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.0861531
X-RAY DIFFRACTIONr_chiral_restr0.0890.2861
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.026595
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021176
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.23→2.29 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.345 108 -
Rwork0.285 2466 -
obs--92.16 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.31770.6165-0.22641.5685-0.0810.3811-0.01570.063-0.17160.17790.0246-0.1593-0.1215-0.1623-0.00890.08720.04570.01970.0718-00.048526.02713.4420.725
22.43580.51930.19661.4802-0.26891.58630.0540.04850.00660.10640.02020.1421-0.08620.0586-0.07420.0895-0.04140.02870.0241-0.00890.0243-1.68311.69236.428
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A207 - 562
2X-RAY DIFFRACTION2B207 - 552

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