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- PDB-9dom: PVTX-405: A Potent, Highly Selective, and Orally Efficacious Mole... -

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Basic information

Entry
Database: PDB / ID: 9dom
TitlePVTX-405: A Potent, Highly Selective, and Orally Efficacious Molecular Glue Degrader of IKZF2 for Cancer Immunotherapy
Components
  • Protein cereblon
  • Zinc finger protein Helios
KeywordsTRANSCRIPTION / Molecular Glue Protein Degrader
Function / homology
Function and homology information


negative regulation of monoatomic ion transmembrane transport / Cul4A-RING E3 ubiquitin ligase complex / locomotory exploration behavior / positive regulation of Wnt signaling pathway / negative regulation of protein-containing complex assembly / positive regulation of protein-containing complex assembly / proteasome-mediated ubiquitin-dependent protein catabolic process / Potential therapeutics for SARS / transmembrane transporter binding / protein ubiquitination ...negative regulation of monoatomic ion transmembrane transport / Cul4A-RING E3 ubiquitin ligase complex / locomotory exploration behavior / positive regulation of Wnt signaling pathway / negative regulation of protein-containing complex assembly / positive regulation of protein-containing complex assembly / proteasome-mediated ubiquitin-dependent protein catabolic process / Potential therapeutics for SARS / transmembrane transporter binding / protein ubiquitination / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / regulation of transcription by RNA polymerase II / perinuclear region of cytoplasm / zinc ion binding / metal ion binding / nucleus / membrane / cytosol / cytoplasm
Similarity search - Function
: / Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / CULT domain / CULT domain profile. / Lon N-terminal domain profile. / Lon protease, N-terminal domain / Lon protease, N-terminal domain superfamily / ATP-dependent protease La (LON) substrate-binding domain / Found in ATP-dependent protease La (LON) ...: / Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / CULT domain / CULT domain profile. / Lon N-terminal domain profile. / Lon protease, N-terminal domain / Lon protease, N-terminal domain superfamily / ATP-dependent protease La (LON) substrate-binding domain / Found in ATP-dependent protease La (LON) / PUA-like superfamily / Zinc finger, C2H2 type / zinc finger / Zinc finger C2H2 type domain profile. / Zinc finger C2H2 superfamily / Zinc finger C2H2 type domain signature. / Zinc finger C2H2-type
Similarity search - Domain/homology
: / Protein cereblon / Zinc finger protein Helios
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.69 Å
AuthorsStrickland, C.O. / Rice, C.T.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Nat Commun / Year: 2025
Title: Development of PVTX-405 as a potent and highly selective molecular glue degrader of IKZF2 for cancer immunotherapy.
Authors: Chen, Z. / Dhruv, H. / Zhang, X. / Rej, R.K. / Bai, L. / McEachern, D. / Kirchhoff, P. / Nagilla, R. / Jolivette, L.J. / Rice, C.T. / Orth, P. / Strickland, C.O. / Priestley, E.S. / ...Authors: Chen, Z. / Dhruv, H. / Zhang, X. / Rej, R.K. / Bai, L. / McEachern, D. / Kirchhoff, P. / Nagilla, R. / Jolivette, L.J. / Rice, C.T. / Orth, P. / Strickland, C.O. / Priestley, E.S. / Mohammad, H.P. / Wang, M. / Wen, B. / Sun, D. / Sui, Z. / Wang, S.
History
DepositionSep 19, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 14, 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: Protein cereblon
B: Zinc finger protein Helios
C: Protein cereblon
D: Zinc finger protein Helios
E: Protein cereblon
F: Zinc finger protein Helios
G: Protein cereblon
H: Zinc finger protein Helios
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,74520
Polymers62,4398
Non-polymers2,30512
Water4,990277
1
A: Protein cereblon
B: Zinc finger protein Helios
hetero molecules


Theoretical massNumber of molelcules
Total (without water)16,1865
Polymers15,6102
Non-polymers5763
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: Protein cereblon
D: Zinc finger protein Helios
hetero molecules


Theoretical massNumber of molelcules
Total (without water)16,1865
Polymers15,6102
Non-polymers5763
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
E: Protein cereblon
F: Zinc finger protein Helios
hetero molecules


Theoretical massNumber of molelcules
Total (without water)16,1865
Polymers15,6102
Non-polymers5763
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
G: Protein cereblon
H: Zinc finger protein Helios
hetero molecules


Theoretical massNumber of molelcules
Total (without water)16,1865
Polymers15,6102
Non-polymers5763
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)45.395, 69.239, 79.857
Angle α, β, γ (deg.)90.00, 90.01, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein
Protein cereblon


Mass: 12309.062 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CRBN, AD-006 / Production host: Escherichia coli (E. coli) / References: UniProt: Q96SW2
#2: Protein/peptide
Zinc finger protein Helios / Ikaros family zinc finger protein 2


Mass: 3300.756 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IKZF2, HELIOS, ZNFN1A2 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9UKS7
#3: Chemical
ChemComp-A1A8N / (3S)-3-(1'-benzyl-6-oxo-6,8-dihydro-2H,7H-spiro[furo[2,3-e]isoindole-3,4'-piperidin]-7-yl)piperidine-2,6-dione


Mass: 445.510 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C26H27N3O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 8 / Source method: isolated from a natural source / Formula: Zn
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 277 / 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: 2.01 Å3/Da / Density % sol: 38.8 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 0.4 M Magnesium chloride 0.1 M TRIS pH 7.5 27% w/v PEG 4000

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Data collection

DiffractionMean temperature: 95 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97622 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Apr 30, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97622 Å / Relative weight: 1
ReflectionResolution: 1.69→79.86 Å / Num. obs: 46939 / % possible obs: 84.8 % / Redundancy: 6.4 % / CC1/2: 0.998 / Rmerge(I) obs: 0.077 / Net I/σ(I): 13.3
Reflection shellResolution: 1.69→1.72 Å / Redundancy: 4.9 % / Rmerge(I) obs: 0.653 / Num. unique obs: 1864 / CC1/2: 0.826

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Processing

Software
NameVersionClassification
REFMAC5.8.0349refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.69→79.86 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.939 / SU B: 3.199 / SU ML: 0.1 / Cross valid method: THROUGHOUT / ESU R: 0.161 / ESU R Free: 0.137 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2342 2166 4.6 %RANDOM
Rwork0.21053 ---
obs0.21164 44747 84.64 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 22.825 Å2
Baniso -1Baniso -2Baniso -3
1-0.19 Å2-0 Å2-0.02 Å2
2---0.29 Å2-0 Å2
3---0.11 Å2
Refinement stepCycle: 1 / Resolution: 1.69→79.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4211 0 140 277 4628
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0124525
X-RAY DIFFRACTIONr_bond_other_d0.0010.0163985
X-RAY DIFFRACTIONr_angle_refined_deg1.9011.6976162
X-RAY DIFFRACTIONr_angle_other_deg0.5031.5929324
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.355533
X-RAY DIFFRACTIONr_dihedral_angle_2_deg20.9991013
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.92410714
X-RAY DIFFRACTIONr_chiral_restr0.0640.2664
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.024914
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02918
X-RAY DIFFRACTIONr_mcbond_it2.0152.3222151
X-RAY DIFFRACTIONr_mcbond_other2.0122.3222151
X-RAY DIFFRACTIONr_mcangle_it2.9883.4652673
X-RAY DIFFRACTIONr_mcangle_other2.9883.4652674
X-RAY DIFFRACTIONr_scbond_it2.3852.5372374
X-RAY DIFFRACTIONr_scbond_other2.3852.5372374
X-RAY DIFFRACTIONr_scangle_other3.6713.7013488
X-RAY DIFFRACTIONr_long_range_B_refined5.440.6725205
X-RAY DIFFRACTIONr_long_range_B_other5.37638.9845160
LS refinement shellResolution: 1.69→1.734 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.364 136 -
Rwork0.36 2668 -
obs--68.47 %

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