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

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Basic information

Entry
Database: PDB / ID: 9fiq
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 / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.86 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)83,3704
Polymers82,2972
Non-polymers1,0732
Water32418
1
A: Ubiquitin carboxyl-terminal hydrolase 7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,6852
Polymers41,1481
Non-polymers5371
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Ubiquitin carboxyl-terminal hydrolase 7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,6852
Polymers41,1481
Non-polymers5371
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)75.754, 70.461, 77.946
Angle α, β, γ (deg.)90, 92.905, 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: 41148.473 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-A1ICV / 3-[[4-oxidanyl-1-[(3~{S},4~{S})-3-phenyl-1-(phenylmethyl)piperidin-4-yl]carbonyl-piperidin-4-yl]methyl]quinazolin-4-one


Mass: 536.664 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C33H36N4O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 18 / 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: 2.52 Å3/Da / Density % sol: 51.28 %
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: ESRF / Beamline: ID29 / Wavelength: 1.0723 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 25, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0723 Å / Relative weight: 1
ReflectionResolution: 2.86→50 Å / Num. obs: 18505 / % possible obs: 96.7 % / Redundancy: 2.9 % / Rmerge(I) obs: 0.066 / Rpim(I) all: 0.047 / Rrim(I) all: 0.081 / Net I/σ(I): 8.9
Reflection shellResolution: 2.86→2.96 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.574 / Mean I/σ(I) obs: 1.7 / Num. unique obs: 1834 / Rpim(I) all: 0.404 / Rrim(I) all: 0.705 / % possible all: 99

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Processing

Software
NameVersionClassification
REFMAC5.8.0425refinement
XDSdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.86→43.726 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.934 / SU B: 21.308 / SU ML: 0.396 / Cross valid method: FREE R-VALUE / ESU R Free: 0.454
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2778 948 5.127 %
Rwork0.1974 17543 -
all0.202 --
obs-18491 96.458 %
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: 91.823 Å2
Baniso -1Baniso -2Baniso -3
1--5.192 Å2-0 Å2-2.297 Å2
2--0.864 Å2-0 Å2
3---4.538 Å2
Refinement stepCycle: LAST / Resolution: 2.86→43.726 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5310 0 80 18 5408
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0125508
X-RAY DIFFRACTIONr_bond_other_d0.0010.0165175
X-RAY DIFFRACTIONr_angle_refined_deg1.6521.8567431
X-RAY DIFFRACTIONr_angle_other_deg0.5581.78411963
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.4295645
X-RAY DIFFRACTIONr_dihedral_angle_2_deg9.478730
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.46610995
X-RAY DIFFRACTIONr_dihedral_angle_6_deg14.74910277
X-RAY DIFFRACTIONr_chiral_restr0.080.2795
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.026349
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021249
X-RAY DIFFRACTIONr_nbd_refined0.2350.21085
X-RAY DIFFRACTIONr_symmetry_nbd_other0.2120.24957
X-RAY DIFFRACTIONr_nbtor_refined0.1910.22529
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0850.23198
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1850.2135
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.1220.25
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1570.212
X-RAY DIFFRACTIONr_nbd_other0.260.242
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2740.25
X-RAY DIFFRACTIONr_mcbond_it7.8788.9582604
X-RAY DIFFRACTIONr_mcbond_other7.8768.9592604
X-RAY DIFFRACTIONr_mcangle_it11.57516.0973241
X-RAY DIFFRACTIONr_mcangle_other11.57616.0993242
X-RAY DIFFRACTIONr_scbond_it8.2299.4612904
X-RAY DIFFRACTIONr_scbond_other8.2289.4612905
X-RAY DIFFRACTIONr_scangle_it12.44817.1284190
X-RAY DIFFRACTIONr_scangle_other12.44717.1264191
X-RAY DIFFRACTIONr_lrange_it17.965108.38322291
X-RAY DIFFRACTIONr_lrange_other17.966108.31322290
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
2.86-2.9340.48700.32213310.3314200.8780.92898.6620.308
2.934-3.0140.422660.29212580.29913500.8840.94898.07410.274
3.014-3.1010.35550.26212520.26613260.9350.9698.56710.244
3.101-3.1960.375730.25811940.26512880.9150.96198.36960.241
3.196-3.30.297590.24611650.24912500.9360.96297.920.227
3.3-3.4150.422680.24311240.25312170.8860.96297.94580.227
3.415-3.5430.309510.24110880.24511730.9350.96397.10140.228
3.543-3.6870.326580.23210270.23711270.9320.96996.27330.227
3.687-3.850.284620.2189600.22210740.9490.97195.15830.219
3.85-4.0360.29610.1979190.20210350.9450.97694.6860.199
4.036-4.2520.29450.1948940.1999930.9430.97694.56190.201
4.252-4.5080.235530.1698370.1739340.9680.98395.28910.182
4.508-4.8150.273310.1528070.1568770.9580.98695.5530.171
4.815-5.1960.232410.1577550.1628370.9660.98595.10160.174
5.196-5.6840.255410.1696590.1737490.9690.98493.45790.187
5.684-6.3410.263320.1946190.1987000.9680.978930.218
6.341-7.2970.245290.1815580.1856100.9690.9896.22950.199
7.297-8.8750.214290.1514790.1545300.9620.98695.84910.182
8.875-12.30.219170.1343750.1384140.9770.98994.6860.161
12.3-43.7260.15870.2712420.2672600.990.94495.76920.309

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