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- PDB-9qje: USP7 Covalently Bound to N-(6-Fluoro-3-nitropyridin-2-yl)-5-(1-me... -

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Basic information

Entry
Database: PDB / ID: 9qje
TitleUSP7 Covalently Bound to N-(6-Fluoro-3-nitropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-amine (GCL36, 7a) with Partial Occupancy
ComponentsUbiquitin carboxyl-terminal hydrolase 7
KeywordsHYDROLASE / Covalent / SNAr / Inhibitor
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
: / BROMIDE ION / DI(HYDROXYETHYL)ETHER / Ubiquitin carboxyl-terminal hydrolase 7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.26 Å
AuthorsStahlecker, J. / Ernst, L.N. / Gehringer, M. / Stehle, T. / Boeckler, F.M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Arch Pharm / Year: 2025
Title: Design, Synthesis, and Molecular Evaluation of S N Ar-Reactive N-(6-Fluoro-3-Nitropyridin-2-yl)Isoquinolin-3-Amines as Covalent USP7 Inhibitors Reveals an Unconventional Binding Mode.
Authors: Ernst, L.N. / Stahlecker, J. / Mier, F. / Serafim, R.A.M. / Wydra, V.R. / Masberg, B. / Jaag, S.J. / Knappe, C. / Lammerhofer, M. / Stehle, T. / Gehringer, M. / Boeckler, F.M.
History
DepositionMar 19, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 10, 2025Provider: repository / Type: Initial release

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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)83,74412
Polymers82,4112
Non-polymers1,33310
Water81145
1
A: Ubiquitin carboxyl-terminal hydrolase 7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,8636
Polymers41,2061
Non-polymers6585
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Ubiquitin carboxyl-terminal hydrolase 7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,8816
Polymers41,2061
Non-polymers6755
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)75.749, 68.816, 77.668
Angle α, β, γ (deg.)90.000, 94.480, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

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Protein , 1 types, 2 molecules AB

#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: 41205.523 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) / References: UniProt: Q93009, ubiquitinyl hydrolase 1

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Non-polymers , 5 types, 55 molecules

#2: Chemical ChemComp-A1I71 / ~{N}-(3-nitropyridin-2-yl)isoquinolin-3-amine


Mass: 347.351 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H15N6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H10O3
#5: Chemical ChemComp-BR / BROMIDE ION


Mass: 79.904 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Br
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 45 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 2.45 Å3/Da / Density % sol: 49.77 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: USP7 (17.5 mg/mL) was incubated with the Compound (500 uM in reservoir solution) prior to crystallization. The reservoir solution contained 0.1 M HEPES pH 7.5, 0.2 M sodium bromide, 22% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, DESY / Beamline: P11 / Wavelength: 1.03321 Å
DetectorType: DECTRIS EIGER2 S 16M / Detector: PIXEL / Date: Dec 18, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.03321 Å / Relative weight: 1
ReflectionResolution: 2.26→50 Å / Num. obs: 37154 / % possible obs: 98.9 % / Redundancy: 7.06 % / Biso Wilson estimate: 78.21 Å2 / CC1/2: 1 / Net I/σ(I): 23.33
Reflection shellResolution: 2.26→2.4 Å / Redundancy: 7.31 % / Mean I/σ(I) obs: 1.02 / Num. unique obs: 5966 / CC1/2: 0.6 / % possible all: 99.2

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.26→43.58 Å / SU ML: 0.3838 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 33.437
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2478 1523 4.11 %
Rwork0.2036 35576 -
obs0.2054 37099 98.88 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 89.8 Å2
Refinement stepCycle: LAST / Resolution: 2.26→43.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5174 0 75 45 5294
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00765352
X-RAY DIFFRACTIONf_angle_d0.88857259
X-RAY DIFFRACTIONf_chiral_restr0.0534804
X-RAY DIFFRACTIONf_plane_restr0.0083949
X-RAY DIFFRACTIONf_dihedral_angle_d15.75271921
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.26-2.330.37471370.34653202X-RAY DIFFRACTION99.32
2.33-2.420.34391390.33383251X-RAY DIFFRACTION99.3
2.42-2.510.38871380.30523223X-RAY DIFFRACTION99.32
2.51-2.630.43841380.3323223X-RAY DIFFRACTION99
2.63-2.770.35911370.27263217X-RAY DIFFRACTION98.47
2.77-2.940.31621370.25413191X-RAY DIFFRACTION98.61
2.94-3.170.3011360.25513178X-RAY DIFFRACTION97.18
3.17-3.480.29011390.2243257X-RAY DIFFRACTION99.71
3.48-3.990.24381400.19013269X-RAY DIFFRACTION99.65
3.99-5.020.19121400.15993274X-RAY DIFFRACTION99.42
5.02-43.580.21571420.1823291X-RAY DIFFRACTION97.75
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)
15.20614528288-0.5905549129420.3584243361132.08941064458-0.01114916870353.52020812910.0982368398638-0.0884584568713-0.7429751510540.02865366588510.02341239107930.8144773703360.271303077141-0.381838052008-0.01929520890460.8602183376580.01761033044160.005673790317630.6034292023040.01207757074810.988343122645-24.29807164217.02683446882-2.10112314636
25.074467144862.78887299061-1.183052282352.964124835791.422394742113.265886412760.06052054398150.029866154043-0.83725710278-0.194169681776-0.470806551353-0.4082093677050.949622931423-0.01323043509690.2966945988691.0171770919-0.02453382183970.1692024896590.7516829367730.1048251759690.914029459064-24.31783579032.488425442476.2628316118
34.68308233796-0.179105558496-0.2537847017191.26250178266-0.2199916252220.8221240417420.0359821518708-0.142412748884-0.623323067142-0.141831453822-0.0498821382984-0.4650883212930.1641553260560.2329098179920.1039041890970.8409951616790.0517163005839-0.06177168006440.6815063601650.07424111726330.898616781054-0.944184441348.01555044165-3.05496417673
46.21411543934-2.395215196321.139923226633.14709469978-0.5160987998141.667496465890.00955516991695-0.08593534654250.697948166152-0.152824064093-0.288544956125-1.83646897660.06534486955790.2043857093920.1994579446150.7623740372430.0177706119119-0.1248530300140.7225995407330.2210365988791.2174736327519.0005130938.8052525104-0.199434850079
56.80461619507-1.65152907610.9249564980964.00229294911.805277881292.33696156833-0.108198810847-0.4588073191770.6709154048890.4041213941040.0672391117459-0.6099769080910.0746006654498-0.04362910142370.0726707923620.7213075285250.00875245999997-0.07521633596230.5673426602560.004930913237340.716501553967-3.6951790279319.68428232190.214303206144
66.38979001299-0.03037493831211.741049506645.147159179470.7010517569641.25762427277-0.00418914523876-0.3431569396680.696579919457-0.013787098634-0.3450254097010.452349317408-0.296788043728-0.1538975228440.1559051623430.778955995888-0.005696589340740.01600820713310.6648845992970.006444673942610.681369243872-17.667939225420.6114520064-0.77431517361
70.250837978726-0.3321369219181.153714646050.463790356653-1.638426854435.810647878580.546555889701-0.51219481137-1.144672703910.5582773687350.5562376559490.07632248879210.403137544318-1.71800964179-0.0210296132480.894142398203-0.171428963801-0.0594586321.14586156469-0.1733023252621.77317311809-36.6082567961-2.29015280891-3.77106087829
84.95100177533-0.1709362543141.438759319215.500773170580.7293918220664.23402297161-0.1938442791540.117585306811-0.181064055981-0.2653839006560.146988179941-0.5104499404240.004998420938710.4331651152280.1229712523810.683007281190.1022698290850.07247661998190.762688404025-0.1127660675460.775427082564-10.66613855054.39654225998-37.4966323768
93.93327786059-0.732523602046-0.04227749128871.91879632649-0.0136956952090.790121618252-0.126479655040.413083882438-0.721780675897-0.1182448916380.04516066498660.4640373402570.212932185776-0.1167523733010.08187455986010.7225397868660.046639034718-0.0256516264840.738231325471-0.1122614326580.890166639743-30.47159909975.00147012383-38.8753428648
104.16578196344.766938280610.7534853771865.773502946121.191790630950.46768485822-0.6924302571630.768470193220.389838774656-0.4734820935210.4007893042831.728633292340.247758197233-0.09836135923980.1385765512410.812600195703-0.0153304975712-0.0603374959920.824206235251-0.03512343742251.17604691503-55.00158410386.17877570207-41.2187759221
115.222997811910.5335479696720.004440629009364.62374620069-1.649295830051.63582313024-0.1530377091490.0702631855172-0.00138841087584-0.07950765231160.173584824440.4512883263780.00550548859780.272761074989-0.00570792150820.636810998030.0808609257081-0.031024594720.638141106678-0.009644068582040.61128195196-30.972780582817.5643540822-38.4659208734
121.93371749255-0.01557445311371.164492674594.823312851032.25309546875.10207574965-0.07765202541310.4025743756730.707211492409-0.3903069099370.123477345098-1.19792007731-0.5689875282420.745592140768-0.01193526560110.8037027305960.0014758649250.04249151700060.951262074886-0.06770613456790.804662837759-13.253893914819.7025263086-41.2534991145
136.2721783028-2.62233718989-0.2556914175434.66421813232-0.6003840252190.813229562080.03858394848850.0594947399513-0.1138590060820.290245834642-0.0251832072806-0.361516483471-0.1265658474590.389311979825-0.009876743216460.6233687890720.0649996150184-0.1527023503650.724601085639-0.1431656041030.627859707274-13.468051770911.3201264886-35.5468595625
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 206 through 269 )AA206 - 2691 - 64
22chain 'A' and (resid 270 through 287 )AA270 - 28765 - 82
33chain 'A' and (resid 288 through 367 )AA288 - 36783 - 162
44chain 'A' and (resid 368 through 397 )AA368 - 397163 - 192
55chain 'A' and (resid 398 through 457 )AA398 - 457193 - 252
66chain 'A' and (resid 458 through 537 )AA458 - 537253 - 323
77chain 'A' and (resid 538 through 554 )AA538 - 554324 - 340
88chain 'B' and (resid 206 through 269 )BF206 - 2691 - 64
99chain 'B' and (resid 270 through 367 )BF270 - 36765 - 162
1010chain 'B' and (resid 368 through 395 )BF368 - 395163 - 190
1111chain 'B' and (resid 396 through 457 )BF396 - 457191 - 250
1212chain 'B' and (resid 458 through 488 )BF458 - 488251 - 278
1313chain 'B' and (resid 489 through 554 )BF489 - 554279 - 336

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