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

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Basic information

Entry
Database: PDB / ID: 9fip
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: 3.06 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)83,1884
Polymers82,2972
Non-polymers8912
Water25214
1
A: Ubiquitin carboxyl-terminal hydrolase 7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,5942
Polymers41,1481
Non-polymers4461
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Ubiquitin carboxyl-terminal hydrolase 7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,5942
Polymers41,1481
Non-polymers4461
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)75.05, 68.28, 77.66
Angle α, β, γ (deg.)90, 92, 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: LYS / End label comp-ID: LYS / Auth asym-ID: A / Label asym-ID: A / Auth seq-ID: 211 - 554 / Label seq-ID: 6 - 349

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: 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-A1ICU / 3-[[4-oxidanyl-1-[(1~{R},2~{R})-2-phenylcyclohexyl]carbonyl-piperidin-4-yl]methyl]quinazolin-4-one


Mass: 445.553 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H31N3O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 14 / 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: 2.42 Å3/Da / Density % sol: 49.1 % / Description: Plates
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: Oct 10, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 3.06→77.61 Å / Num. obs: 14565 / % possible obs: 96.9 % / Redundancy: 2.8 % / Rmerge(I) obs: 0.108 / Net I/σ(I): 7.6
Reflection shellResolution: 3.06→3.14 Å / Redundancy: 3 % / Rmerge(I) obs: 0.619 / Num. unique obs: 1101 / % possible all: 98.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0425refinement
XDSdata reduction
XSCALEdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.06→77.61 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.926 / SU B: 25.815 / SU ML: 0.439 / Cross valid method: FREE R-VALUE / ESU R Free: 0.525
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2639 731 5.037 %
Rwork0.1694 13783 -
all0.174 --
obs-14514 96.586 %
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: 91.285 Å2
Baniso -1Baniso -2Baniso -3
1--4.248 Å2-0 Å2-3.557 Å2
2---1.747 Å20 Å2
3---6.229 Å2
Refinement stepCycle: LAST / Resolution: 3.06→77.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5410 0 66 14 5490
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0125596
X-RAY DIFFRACTIONr_bond_other_d0.0010.0165247
X-RAY DIFFRACTIONr_angle_refined_deg1.5251.877550
X-RAY DIFFRACTIONr_angle_other_deg0.531.80212130
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.2795660
X-RAY DIFFRACTIONr_dihedral_angle_2_deg9.272527
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.295101012
X-RAY DIFFRACTIONr_dihedral_angle_6_deg14.11210285
X-RAY DIFFRACTIONr_chiral_restr0.0740.2803
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.026477
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021269
X-RAY DIFFRACTIONr_nbd_refined0.2230.21083
X-RAY DIFFRACTIONr_symmetry_nbd_other0.2150.25015
X-RAY DIFFRACTIONr_nbtor_refined0.1880.22565
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0840.23026
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1640.2134
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0580.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1970.29
X-RAY DIFFRACTIONr_nbd_other0.1940.244
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.3790.25
X-RAY DIFFRACTIONr_xyhbond_nbd_other0.2370.21
X-RAY DIFFRACTIONr_mcbond_it7.4838.7682658
X-RAY DIFFRACTIONr_mcbond_other7.4678.7692658
X-RAY DIFFRACTIONr_mcangle_it11.22915.743312
X-RAY DIFFRACTIONr_mcangle_other11.22715.7423313
X-RAY DIFFRACTIONr_scbond_it8.3699.5192938
X-RAY DIFFRACTIONr_scbond_other8.3689.5182939
X-RAY DIFFRACTIONr_scangle_it13.05417.1444238
X-RAY DIFFRACTIONr_scangle_other13.05317.1444239
X-RAY DIFFRACTIONr_lrange_it18.052106.29622504
X-RAY DIFFRACTIONr_lrange_other18.052106.29522505
X-RAY DIFFRACTIONr_ncsr_local_group_10.2230.059312
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)Weight position
11AX-RAY DIFFRACTIONLocal ncs0.222960.05005
12AX-RAY DIFFRACTIONLocal ncs0.222960.05005
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.06-3.1390.459530.2841038X-RAY DIFFRACTION97.9354
3.139-3.2250.337610.256981X-RAY DIFFRACTION98.1168
3.225-3.3190.3570.234959X-RAY DIFFRACTION97.9749
3.319-3.4210.305560.22961X-RAY DIFFRACTION98.3559
3.421-3.5330.306400.215906X-RAY DIFFRACTION97.6264
3.533-3.6560.331520.213858X-RAY DIFFRACTION96.2963
3.656-3.7940.329380.203848X-RAY DIFFRACTION95.1665
3.794-3.9480.279470.179795X-RAY DIFFRACTION96.3387
3.948-4.1240.287400.154777X-RAY DIFFRACTION96.1176
4.124-4.3240.224420.137729X-RAY DIFFRACTION94.4853
4.324-4.5570.173400.13697X-RAY DIFFRACTION94.7301
4.557-4.8330.18300.12678X-RAY DIFFRACTION96.0651
4.833-5.1650.222300.127631X-RAY DIFFRACTION95.9361
5.165-5.5770.232320.153583X-RAY DIFFRACTION95.3488
5.577-6.1060.473270.18544X-RAY DIFFRACTION96.4527
6.106-6.8210.271270.177502X-RAY DIFFRACTION95.8333
6.821-7.8660.227230.14436X-RAY DIFFRACTION96.6316
7.866-9.610.21190.128373X-RAY DIFFRACTION95.3771
9.61-13.4870.217100.135304X-RAY DIFFRACTION97.2136
13.487-77.610.17670.28183X-RAY DIFFRACTION98.4456

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