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- PDB-9n9y: Crystal structure of truncated USP1:UAF1 in complex with compound 18 -

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Basic information

Entry
Database: PDB / ID: 9n9y
TitleCrystal structure of truncated USP1:UAF1 in complex with compound 18
Components
  • Ubiquitin carboxyl-terminal hydrolase 1, N-terminal fragment,Ubiquitin carboxyl-terminal hydrolase 1
  • WD repeat-containing protein 48
KeywordsHYDROLASE/INHIBITOR / ubiquitin / cysteine protease / allosteric inhibitor / HYDROLASE / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


regulation of protein monoubiquitination / positive regulation of error-prone translesion synthesis / Signaling by cytosolic PDGFRA and PDGFRB fusion proteins / monoubiquitinated protein deubiquitination / deubiquitinase activator activity / skeletal system morphogenesis / skin development / seminiferous tubule development / homeostasis of number of cells / protein deubiquitination ...regulation of protein monoubiquitination / positive regulation of error-prone translesion synthesis / Signaling by cytosolic PDGFRA and PDGFRB fusion proteins / monoubiquitinated protein deubiquitination / deubiquitinase activator activity / skeletal system morphogenesis / skin development / seminiferous tubule development / homeostasis of number of cells / protein deubiquitination / single fertilization / embryonic organ development / positive regulation of double-strand break repair via homologous recombination / regulation of DNA repair / response to UV / positive regulation of epithelial cell proliferation / ubiquitin binding / skeletal system development / positive regulation of receptor signaling pathway via JAK-STAT / Fanconi Anemia Pathway / Recognition of DNA damage by PCNA-containing replication complex / double-strand break repair via homologous recombination / regulation of protein stability / multicellular organism growth / late endosome / peptidase activity / single-stranded DNA binding / double-stranded DNA binding / spermatogenesis / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / lysosome / Ub-specific processing proteases / cysteine-type endopeptidase activity / DNA repair / intracellular membrane-bounded organelle / DNA damage response / proteolysis / DNA binding / nucleoplasm / nucleus / cytosol / cytoplasm
Similarity search - Function
WDR48/Bun107 / Ubiquitin specific peptidase 1 / : / Domain of unknown function (DUF3337) / : / 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 ...WDR48/Bun107 / Ubiquitin specific peptidase 1 / : / Domain of unknown function (DUF3337) / : / 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 / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
: / Ubiquitin carboxyl-terminal hydrolase 1 / WD repeat-containing protein 48
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.15 Å
AuthorsWhittington, D.A.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2025
Title: Discovery of TNG-6132, a potent, selective, and orally bioavailable USP1 inhibitor.
Authors: Throner, S. / Feng, T. / Andersen, J.N. / Bandi, M. / Engel, J.L. / Gong, S. / Gotur, D. / Gu, L. / Huang, A. / Lazarides, K. / Maxwell, J.P. / McCarren, P. / McMillan, B.J. / Pham, T.V. / ...Authors: Throner, S. / Feng, T. / Andersen, J.N. / Bandi, M. / Engel, J.L. / Gong, S. / Gotur, D. / Gu, L. / Huang, A. / Lazarides, K. / Maxwell, J.P. / McCarren, P. / McMillan, B.J. / Pham, T.V. / Simoneau, A. / Tsai, A. / Whittington, D.A. / Wilker, E. / Zhang, M. / Zhang, W.
History
DepositionFeb 11, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 14, 2025Provider: repository / Type: Initial release
Revision 1.1May 21, 2025Group: Database references / Category: citation / Item: _citation.journal_volume

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: WD repeat-containing protein 48
B: Ubiquitin carboxyl-terminal hydrolase 1, N-terminal fragment,Ubiquitin carboxyl-terminal hydrolase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)107,5454
Polymers106,9742
Non-polymers5712
Water18010
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)123.200, 161.880, 160.480
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222
Space group name HallI22
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z
#4: -x,-y,z
#5: x+1/2,y+1/2,z+1/2
#6: x+1/2,-y+1/2,-z+1/2
#7: -x+1/2,y+1/2,-z+1/2
#8: -x+1/2,-y+1/2,z+1/2

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Components

#1: Protein WD repeat-containing protein 48 / USP1-associated factor 1 / WD repeat endosomal protein / p80


Mass: 64019.430 Da / Num. of mol.: 1 / Fragment: residues 1-563
Source method: isolated from a genetically manipulated source
Details: C-terminal TEV sequence after cleavage: ENLYFQ / Source: (gene. exp.) Homo sapiens (human) / Gene: WDR48, KIAA1449, UAF1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q8TAF3
#2: Protein Ubiquitin carboxyl-terminal hydrolase 1, N-terminal fragment,Ubiquitin carboxyl-terminal hydrolase 1 / Deubiquitinating enzyme 1 / hUBP / Ubiquitin thioesterase 1 / Ubiquitin-specific-processing protease 1


Mass: 42954.496 Da / Num. of mol.: 1
Mutation: residues 1-84 deleted, residues 223-440 replaced with GSGSGSGSGS, residues 606-738 deleted
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: USP1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: O94782, ubiquitinyl hydrolase 1
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-A1BWW / 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-({4-[1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}methyl)-5H-pyrrolo[3,2-d]pyrimidine


Mass: 505.494 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H22F3N7O / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 10 / 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: 3.74 Å3/Da / Density % sol: 67.11 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: 1M sodium citrate (pH 6.5)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08B1-1 / Wavelength: 1.18064 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Aug 15, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.18064 Å / Relative weight: 1
ReflectionResolution: 3.15→49.43 Å / Num. obs: 13245 / % possible obs: 46.4 % / Redundancy: 6.4 % / Biso Wilson estimate: 87.01 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.095 / Net I/σ(I): 12.1
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Diffraction-ID
3.15-3.370.4343.61930.8761
8.91-49.435.90.03136.513390.9991

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
REFMAC5.8.0267refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.15→49.43 Å / SU ML: 0.4099 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 34.2497
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2915 677 5.11 %
Rwork0.2371 12560 -
obs0.2399 13237 47.13 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 83.98 Å2
Refinement stepCycle: LAST / Resolution: 3.15→49.43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6691 0 38 10 6739
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00176860
X-RAY DIFFRACTIONf_angle_d0.47519297
X-RAY DIFFRACTIONf_chiral_restr0.04081063
X-RAY DIFFRACTIONf_plane_restr0.00331173
X-RAY DIFFRACTIONf_dihedral_angle_d11.67782528
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.15-3.390.413990.4019220X-RAY DIFFRACTION4.14
3.4-3.740.3542430.3139746X-RAY DIFFRACTION14.25
3.74-4.280.3571220.2511823X-RAY DIFFRACTION35
4.28-5.390.29612110.23334274X-RAY DIFFRACTION79.75
5.39-49.430.26932920.23135497X-RAY DIFFRACTION99.79

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