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

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Basic information

Entry
Database: PDB / ID: 9fis
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 NF-kappaB transcription factor activity ...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 NF-kappaB transcription factor activity / negative regulation of gene expression via chromosomal CpG island methylation / protein deubiquitination / negative regulation of gluconeogenesis / negative regulation of TORC1 signaling / transcription-coupled nucleotide-excision repair / 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 / PML body / regulation of protein stability / 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 / Ub-specific processing proteases / protein stabilization / 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 / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.77 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

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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)85,0304
Polymers83,9292
Non-polymers1,1012
Water1,20767
1
A: Ubiquitin carboxyl-terminal hydrolase 7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,5152
Polymers41,9641
Non-polymers5511
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Ubiquitin carboxyl-terminal hydrolase 7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,5152
Polymers41,9641
Non-polymers5511
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)74.84, 70.58, 78.59
Angle α, β, γ (deg.)90, 92.96, 90
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: 41964.406 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 BL21(DE3) (bacteria) / Variant (production host): pLysS / References: UniProt: Q93009, ubiquitinyl hydrolase 1
#2: Chemical ChemComp-A1ICW / 3-[[4-oxidanyl-1-[(3~{R},4~{R})-3-phenyl-1-(2-phenylethyl)piperidin-4-yl]carbonyl-piperidin-4-yl]methyl]quinazolin-4-one


Mass: 550.691 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H38N4O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 67 / 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: 2.47 Å3/Da / Density % sol: 50.2 %
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: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9763 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: May 17, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 2.77→52.78 Å / Num. obs: 20568 / % possible obs: 97.9 % / Redundancy: 3.2 % / Rmerge(I) obs: 0.127 / Net I/σ(I): 6.8
Reflection shellResolution: 2.77→2.84 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.768 / Mean I/σ(I) obs: 1.5 / Num. unique obs: 1516 / % possible all: 98.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0425refinement
XDSdata reduction
XSCALEdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.77→52.78 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.934 / SU B: 15.914 / SU ML: 0.302 / Cross valid method: FREE R-VALUE / ESU R Free: 0.369
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2433 1050 5.114 %
Rwork0.1848 19480 -
all0.188 --
obs-20530 97.646 %
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: 69.819 Å2
Baniso -1Baniso -2Baniso -3
1-0.374 Å20 Å22.204 Å2
2--0.629 Å20 Å2
3----1.224 Å2
Refinement stepCycle: LAST / Resolution: 2.77→52.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5415 0 82 67 5564
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0125619
X-RAY DIFFRACTIONr_bond_other_d0.0010.0165244
X-RAY DIFFRACTIONr_angle_refined_deg1.6891.8527586
X-RAY DIFFRACTIONr_angle_other_deg0.581.78212125
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9655663
X-RAY DIFFRACTIONr_dihedral_angle_2_deg14.395730
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.654101007
X-RAY DIFFRACTIONr_dihedral_angle_6_deg14.71810286
X-RAY DIFFRACTIONr_chiral_restr0.0850.2808
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.026523
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021279
X-RAY DIFFRACTIONr_nbd_refined0.2210.2886
X-RAY DIFFRACTIONr_symmetry_nbd_other0.2030.24552
X-RAY DIFFRACTIONr_nbtor_refined0.1830.22570
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0860.23141
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1440.296
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0960.21
X-RAY DIFFRACTIONr_nbd_other0.1640.215
X-RAY DIFFRACTIONr_mcbond_it6.0796.6582667
X-RAY DIFFRACTIONr_mcbond_other6.0786.6582667
X-RAY DIFFRACTIONr_mcangle_it9.06711.9773325
X-RAY DIFFRACTIONr_mcangle_other9.06511.9793326
X-RAY DIFFRACTIONr_scbond_it6.9757.3322952
X-RAY DIFFRACTIONr_scbond_other6.9747.3322953
X-RAY DIFFRACTIONr_scangle_it10.90313.1764261
X-RAY DIFFRACTIONr_scangle_other10.90113.1744262
X-RAY DIFFRACTIONr_lrange_it15.67980.39422096
X-RAY DIFFRACTIONr_lrange_other15.6880.40222085
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.77-2.8420.434750.3011424X-RAY DIFFRACTION97.9739
2.842-2.9190.412870.3241380X-RAY DIFFRACTION98.0615
2.919-3.0040.402710.31377X-RAY DIFFRACTION98.5705
3.004-3.0960.285770.2811325X-RAY DIFFRACTION98.386
3.096-3.1970.413570.2581291X-RAY DIFFRACTION98.1077
3.197-3.3090.244620.2341242X-RAY DIFFRACTION98.2668
3.309-3.4330.301660.2181189X-RAY DIFFRACTION97.5894
3.433-3.5730.278470.2161148X-RAY DIFFRACTION96.5267
3.573-3.7310.221610.1941097X-RAY DIFFRACTION97.3928
3.731-3.9120.273550.1961047X-RAY DIFFRACTION96.0767
3.912-4.1220.267580.18997X-RAY DIFFRACTION97.1455
4.122-4.3710.182430.151961X-RAY DIFFRACTION98.0469
4.371-4.670.198490.126887X-RAY DIFFRACTION96.6942
4.67-5.0410.159460.119839X-RAY DIFFRACTION97.3597
5.041-5.5170.236440.137760X-RAY DIFFRACTION97.9294
5.517-6.160.224440.164703X-RAY DIFFRACTION98.1603
6.16-7.0970.254410.173618X-RAY DIFFRACTION98.8006
7.097-8.6530.184250.151545X-RAY DIFFRACTION98.7868
8.653-12.0760.127250.127414X-RAY DIFFRACTION97.3392
12.076-52.780.263170.216236X-RAY DIFFRACTION91.3357

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