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- PDB-8d4z: Crystal structure of USP7 in complex with allosteric inhibitor FX... -

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Basic information

Entry
Database: PDB / ID: 8d4z
TitleCrystal structure of USP7 in complex with allosteric inhibitor FX1-3763
ComponentsUbiquitin carboxyl-terminal hydrolase 7
KeywordsHYDROLASE/INHIBITOR / USP7 / ALLOSTERIC / INHIBITOR / HYDROLASE / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


regulation of telomere capping / : / 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 / : / 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
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 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
Chem-QBL / Ubiquitin carboxyl-terminal hydrolase 7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.26 Å
AuthorsBell, J.A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: To Be Published
Title: Novel USP7 inhibitors demonstrate potent anti-cancer activity in models of AML, synergy with BCL2 inhibition, and a differentiated mechanism of action
Authors: Futran, A.S. / Lu, T. / Amberg-Johnson, K. / Xu, J. / Yang, X. / He, S. / Boyce, S. / Bell, J. / Pelletier, R. / Suzuki, T. / Huang, X. / Qian, H. / Fang, L. / Xing, L. / Xu, Z. / Kurtz, S.E. ...Authors: Futran, A.S. / Lu, T. / Amberg-Johnson, K. / Xu, J. / Yang, X. / He, S. / Boyce, S. / Bell, J. / Pelletier, R. / Suzuki, T. / Huang, X. / Qian, H. / Fang, L. / Xing, L. / Xu, Z. / Kurtz, S.E. / Tyner, J.W. / Tang, W. / Guo, T. / Akinsanya, K. / Madge, D. / Jensen, K.
History
DepositionJun 3, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 20, 2023Provider: 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)85,1295
Polymers84,1032
Non-polymers1,0263
Water1,820101
1
A: Ubiquitin carboxyl-terminal hydrolase 7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,5182
Polymers42,0511
Non-polymers4671
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Ubiquitin carboxyl-terminal hydrolase 7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,6113
Polymers42,0511
Non-polymers5592
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)70.235, 65.506, 85.086
Angle α, β, γ (deg.)90.000, 94.700, 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: 42051.484 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-QBL / 1-({(7M)-7-[1-(azetidin-3-yl)-6-chloro-1,2,3,4-tetrahydroquinolin-8-yl]thieno[3,2-b]pyridin-2-yl}methyl)pyrrolidine-2,5-dione


Mass: 466.983 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H23ClN4O2S / Feature type: SUBJECT OF INVESTIGATION
#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: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 101 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.32 Å3/Da / Density % sol: 46.97 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 0.10 M Bis-Tris-Propane pH 8.50, 0.10 M K-formate, 26.0 % (w/v) PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, DESY / Beamline: P11 / Wavelength: 1.0332 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Sep 5, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 2.26→70 Å / Num. obs: 36172 / % possible obs: 99.6 % / Redundancy: 3.5 % / CC1/2: 0.998 / Rmerge(I) obs: 0.043 / Rpim(I) all: 0.026 / Rrim(I) all: 0.051 / Net I/σ(I): 12.6 / Num. measured all: 127599 / Scaling rejects: 224
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.26-2.3330.457975632020.8780.3030.552296.6
9.04-703.30.03220366150.9960.0210.03930.299.7

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimless0.7.4data scaling
PDB_EXTRACT3.27data extraction
PRIME-Xrefinement
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5n9r

5n9r


Resolution: 2.26→56.3 Å / Cross valid method: THROUGHOUT
RfactorNum. reflection% reflectionSelection details
Rfree0.26 1808 4.9 %random
Rwork0.203 ---
obs-36172 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 1 Å / VDW probe radii: 1.4 Å / Bsol: 64.1 Å2 / ksol: 0.327 e/Å3
Displacement parametersBiso max: 166.59 Å2 / Biso mean: 69.1612 Å2 / Biso min: 29.92 Å2
Refinement stepCycle: LAST / Resolution: 2.26→56.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5422 0 70 101 5593

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