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- PDB-6f5h: Crystal structure of USP7 in complex with a 4-hydroxypiperidine b... -

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Basic information

Entry
Database: PDB / ID: 6f5h
TitleCrystal structure of USP7 in complex with a 4-hydroxypiperidine based inhibitor
ComponentsUbiquitin carboxyl-terminal hydrolase 7
KeywordsHYDROLASE / USP7 / reversible / inhibitor / selective
Function / homology
Function and homology information


regulation of telomere capping / positive regulation of DNA demethylation / monoubiquitinated protein deubiquitination / regulation of retrograde transport, endosome to Golgi / deubiquitinase activity / negative regulation of gene expression via chromosomal CpG island methylation / regulation of DNA-binding transcription factor activity / K48-linked deubiquitinase activity / symbiont-mediated disruption of host cell PML body / negative regulation of NF-kappaB transcription factor activity ...regulation of telomere capping / positive regulation of DNA demethylation / monoubiquitinated protein deubiquitination / regulation of retrograde transport, endosome to Golgi / deubiquitinase activity / negative regulation of gene expression via chromosomal CpG island methylation / regulation of DNA-binding transcription factor activity / 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 / 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 / rhythmic process / Regulation of TP53 Degradation / p53 binding / chromosome / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / protein stabilization / protein ubiquitination / nuclear body / Ub-specific processing proteases / 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-CQ5 / Ubiquitin carboxyl-terminal hydrolase 7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.16 Å
AuthorsHarrison, T. / Gavory, G. / O'Dowd, C. / Helm, M. / Flasz, J. / Dossang, A. / Hughes, C. / Cassidy, E. / McClelland, K. / Odrzywol, E. ...Harrison, T. / Gavory, G. / O'Dowd, C. / Helm, M. / Flasz, J. / Dossang, A. / Hughes, C. / Cassidy, E. / McClelland, K. / Odrzywol, E. / Page, N. / Barker, O. / Miel, H. / Feutron-Burton, S. / Rountree, J.S.S.
CitationJournal: ACS Med Chem Lett / Year: 2018
Title: Identification and Structure-Guided Development of Pyrimidinone Based USP7 Inhibitors.
Authors: O'Dowd, C.R. / Helm, M.D. / Rountree, J.S.S. / Flasz, J.T. / Arkoudis, E. / Miel, H. / Hewitt, P.R. / Jordan, L. / Barker, O. / Hughes, C. / Rozycka, E. / Cassidy, E. / McClelland, K. / ...Authors: O'Dowd, C.R. / Helm, M.D. / Rountree, J.S.S. / Flasz, J.T. / Arkoudis, E. / Miel, H. / Hewitt, P.R. / Jordan, L. / Barker, O. / Hughes, C. / Rozycka, E. / Cassidy, E. / McClelland, K. / Odrzywol, E. / Page, N. / Feutren-Burton, S. / Dvorkin, S. / Gavory, G. / Harrison, T.
History
DepositionDec 1, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 11, 2018Provider: repository / Type: Initial release

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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 carboxyl-terminal hydrolase 7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)84,3278
Polymers83,0122
Non-polymers1,3156
Water7,278404
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2150 Å2
ΔGint-53 kcal/mol
Surface area32240 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.865, 67.328, 80.686
Angle α, β, γ (deg.)90.000, 105.060, 90.000
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: 41505.855 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
#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.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-CQ5 / 3-[[4-oxidanyl-1-[(3~{R})-3-phenylbutanoyl]piperidin-4-yl]methyl]-6-(2-pyrrolidin-1-ylethylamino)pyrimidin-4-one


Mass: 467.604 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H37N5O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 404 / 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 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop / Details: PEG 4000, Tris, Li2-Sulfate, pH 7.75

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-1 / Wavelength: 0.965 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Jan 27, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.965 Å / Relative weight: 1
ReflectionResolution: 2.16→29.95 Å / Num. obs: 39952 / % possible obs: 95.9 % / Redundancy: 2.4 % / Rrim(I) all: 0.11 / Net I/σ(I): 6.4
Reflection shellResolution: 2.16→2.28 Å / Redundancy: 2.4 % / Mean I/σ(I) obs: 1.4 / Num. unique obs: 5872 / Rrim(I) all: 0.67 / % possible all: 96.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0189refinement
PDB_EXTRACT3.24data extraction
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementResolution: 2.16→29.95 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.92 / SU B: 17.096 / SU ML: 0.221 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.304 / ESU R Free: 0.235
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2624 1958 4.9 %RANDOM
Rwork0.2021 ---
obs0.205 37973 95.53 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 127.29 Å2 / Biso mean: 55.33 Å2 / Biso min: 32.01 Å2
Baniso -1Baniso -2Baniso -3
1-2.46 Å2-0 Å20.78 Å2
2---2.49 Å2-0 Å2
3----0.35 Å2
Refinement stepCycle: final / Resolution: 2.16→29.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5600 0 89 404 6093
Biso mean--54.46 57.54 -
Num. residues----687
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0195811
X-RAY DIFFRACTIONr_bond_other_d0.0020.025278
X-RAY DIFFRACTIONr_angle_refined_deg1.371.9747834
X-RAY DIFFRACTIONr_angle_other_deg0.961312325
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7615683
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.84624.916299
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.826151054
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.1681529
X-RAY DIFFRACTIONr_chiral_restr0.0840.2829
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.026386
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021147
LS refinement shellResolution: 2.16→2.216 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.326 151 -
Rwork0.303 2771 -
all-2922 -
obs--95.77 %
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)
12.24670.47680.00621.5462-0.02340.8216-0.00280.0503-0.13020.07150.001-0.1005-0.0301-0.05220.00190.1306-0.00980.09320.32190.00490.086226.613.2851.246
22.29480.43630.38111.8392-0.06461.69760.05920.00820.00010.0514-0.00210.1621-0.0333-0.0675-0.0570.1504-0.01390.10880.3778-0.00630.0898-1.69412.04235.798
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A207 - 555
2X-RAY DIFFRACTION2B208 - 551

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