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- PDB-7b4n: Structural basis of reactivation of oncogenic p53 mutants by a sm... -

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Basic information

Entry
Database: PDB / ID: 7b4n
TitleStructural basis of reactivation of oncogenic p53 mutants by a small molecule: methylene quinuclidinone (MQ). Human wild-type p53DBD bound to DNA and MQ: wt-DNA-MQ (II)
Components
  • Cellular tumor antigen p53
  • DNA target
KeywordsTRANSCRIPTION / P53 / TUMOR SUPPRESSOR / DNA BINDING PROTEIN / PROTEIN DNA COMPLEX / MICHAEL ACCEPTOR / MICHAEL REACTION / PROTEIN-DRUG COMPLEX / PROTEIN-DNA-DRUG COMPLEX / LOOP-SHEET-HELIX MOTIF / DNA TARGET / ACTIVATOR / HOOGSTEEN BASE-PAIRING
Function / homology
Function and homology information


negative regulation of helicase activity / Loss of function of TP53 in cancer due to loss of tetramerization ability / Regulation of TP53 Expression / signal transduction by p53 class mediator / negative regulation of G1 to G0 transition / negative regulation of glucose catabolic process to lactate via pyruvate / Transcriptional activation of cell cycle inhibitor p21 / regulation of intrinsic apoptotic signaling pathway by p53 class mediator / negative regulation of pentose-phosphate shunt / ATP-dependent DNA/DNA annealing activity ...negative regulation of helicase activity / Loss of function of TP53 in cancer due to loss of tetramerization ability / Regulation of TP53 Expression / signal transduction by p53 class mediator / negative regulation of G1 to G0 transition / negative regulation of glucose catabolic process to lactate via pyruvate / Transcriptional activation of cell cycle inhibitor p21 / regulation of intrinsic apoptotic signaling pathway by p53 class mediator / negative regulation of pentose-phosphate shunt / ATP-dependent DNA/DNA annealing activity / Activation of NOXA and translocation to mitochondria / regulation of cell cycle G2/M phase transition / oligodendrocyte apoptotic process / negative regulation of miRNA processing / intrinsic apoptotic signaling pathway in response to hypoxia / positive regulation of thymocyte apoptotic process / oxidative stress-induced premature senescence / regulation of tissue remodeling / positive regulation of mitochondrial membrane permeability / regulation of fibroblast apoptotic process / cellular response to actinomycin D / germ cell nucleus / bone marrow development / circadian behavior / T cell proliferation involved in immune response / positive regulation of programmed necrotic cell death / regulation of mitochondrial membrane permeability involved in apoptotic process / histone deacetylase regulator activity / : / RUNX3 regulates CDKN1A transcription / TP53 Regulates Transcription of Death Receptors and Ligands / TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain / Activation of PUMA and translocation to mitochondria / mRNA transcription / negative regulation of glial cell proliferation / Regulation of TP53 Activity through Association with Co-factors / regulation of DNA damage response, signal transduction by p53 class mediator / negative regulation of neuroblast proliferation / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / mitochondrial DNA repair / T cell lineage commitment / thymocyte apoptotic process / ER overload response / TP53 Regulates Transcription of Caspase Activators and Caspases / cardiac septum morphogenesis / B cell lineage commitment / entrainment of circadian clock by photoperiod / negative regulation of DNA replication / negative regulation of mitophagy / Zygotic genome activation (ZGA) / Association of TriC/CCT with target proteins during biosynthesis / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / PI5P Regulates TP53 Acetylation / necroptotic process / negative regulation of telomere maintenance via telomerase / positive regulation of release of cytochrome c from mitochondria / SUMOylation of transcription factors / TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain / TFIID-class transcription factor complex binding / intrinsic apoptotic signaling pathway by p53 class mediator / negative regulation of reactive oxygen species metabolic process / rRNA transcription / Transcriptional Regulation by VENTX / cellular response to UV-C / viral process / replicative senescence / neuroblast proliferation / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / general transcription initiation factor binding / positive regulation of RNA polymerase II transcription preinitiation complex assembly / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / Pyroptosis / chromosome organization / positive regulation of execution phase of apoptosis / hematopoietic stem cell differentiation / embryonic organ development / type II interferon-mediated signaling pathway / response to X-ray / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / somitogenesis / hematopoietic progenitor cell differentiation / negative regulation of stem cell proliferation / core promoter sequence-specific DNA binding / glial cell proliferation / cellular response to glucose starvation / negative regulation of fibroblast proliferation / mitophagy / cis-regulatory region sequence-specific DNA binding / Regulation of TP53 Activity through Acetylation / positive regulation of intrinsic apoptotic signaling pathway / negative regulation of proteolysis / response to salt stress / mitotic G1 DNA damage checkpoint signaling / cardiac muscle cell apoptotic process / transcription repressor complex / gastrulation / 14-3-3 protein binding / MDM2/MDM4 family protein binding / positive regulation of cardiac muscle cell apoptotic process / transforming growth factor beta receptor signaling pathway
Similarity search - Function
Cellular tumor antigen p53, transactivation domain 2 / Transactivation domain 2 / p53 transactivation domain / P53 transactivation motif / : / p53 family signature. / p53, tetramerisation domain / P53 tetramerisation motif / p53, DNA-binding domain / P53 DNA-binding domain ...Cellular tumor antigen p53, transactivation domain 2 / Transactivation domain 2 / p53 transactivation domain / P53 transactivation motif / : / p53 family signature. / p53, tetramerisation domain / P53 tetramerisation motif / p53, DNA-binding domain / P53 DNA-binding domain / p53 tumour suppressor family / p53-like tetramerisation domain superfamily / p53/RUNT-type transcription factor, DNA-binding domain superfamily / p53-like transcription factor, DNA-binding
Similarity search - Domain/homology
FORMIC ACID / (2~{R})-2-methyl-1-azabicyclo[2.2.2]octan-3-one / (2~{S})-2-methyl-1-azabicyclo[2.2.2]octan-3-one / DNA / DNA (> 10) / Cellular tumor antigen p53
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.32 Å
AuthorsRozenberg, H. / Diskin-Posner, Y. / Degtjarik, O. / Shakked, Z.
Funding support1items
OrganizationGrant numberCountry
Aprea Therapeutics AB
CitationJournal: Nat Commun / Year: 2021
Title: Structural basis of reactivation of oncogenic p53 mutants by a small molecule: methylene quinuclidinone (MQ).
Authors: Degtjarik, O. / Golovenko, D. / Diskin-Posner, Y. / Abrahmsen, L. / Rozenberg, H. / Shakked, Z.
History
DepositionDec 2, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 8, 2021Provider: repository / Type: Initial release
Revision 1.1Dec 15, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Cellular tumor antigen p53
B: DNA target
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,7458
Polymers26,1702
Non-polymers5756
Water5,296294
1
A: Cellular tumor antigen p53
B: DNA target
hetero molecules

A: Cellular tumor antigen p53
B: DNA target
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,49016
Polymers52,3404
Non-polymers1,15012
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_758-x+2,y,-z+31
Unit cell
Length a, b, c (Å)137.771, 49.982, 34.025
Angle α, β, γ (deg.)90.000, 93.233, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z

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Components

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Protein / DNA chain , 2 types, 2 molecules AB

#1: Protein Cellular tumor antigen p53 / Antigen NY-CO-13 / Phosphoprotein p53 / Tumor suppressor p53


Mass: 22505.582 Da / Num. of mol.: 1 / Fragment: p53 human DNA binding domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TP53, P53 / Plasmid: pET-27-b / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P04637
#2: DNA chain DNA target


Mass: 3664.380 Da / Num. of mol.: 1 / Fragment: p53 DNA target / Mutation: ' / Source method: obtained synthetically / Details: IDT: Integrated DNA Technology / Source: (synth.) synthetic construct (others)

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Non-polymers , 5 types, 300 molecules

#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-QN8 / (2~{R})-2-methyl-1-azabicyclo[2.2.2]octan-3-one


Mass: 139.195 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H13NO / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-QNN / (2~{S})-2-methyl-1-azabicyclo[2.2.2]octan-3-one


Mass: 139.195 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H13NO / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-FMT / FORMIC ACID


Mass: 46.025 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: CH2O2
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 294 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY
Nonpolymer detailsTwo enantiomers, QNN and QN8 are produced by addition reaction of the michael acceptor compound "2- ...Two enantiomers, QNN and QN8 are produced by addition reaction of the michael acceptor compound "2-methylenequinuclidin-3-one" with cysteine or lysine. As such, QNN and QN8 bind covalently to the thiol group of cysteine or amino group of lysine. The chiral definitions of QNN and QN8 bound to cysteines are reversed to that of the pseudo free ligands.

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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: 2.23 Å3/Da / Density % sol: 44.96 % / Mosaicity: 0.244 °
Crystal growTemperature: 292 K / Method: evaporation
Details: Protein/DNA ratio 1:2.4, 0.1M TRIS pH=8.5, 2% Tacsimate(TM) pH=8.0, 16% w/v PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.976 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 27, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 1.32→100 Å / Num. obs: 53678 / % possible obs: 99.3 % / Redundancy: 10.7 % / Rmerge(I) obs: 0.06 / Rpim(I) all: 0.018 / Rrim(I) all: 0.063 / Χ2: 1.006 / Net I/σ(I): 8.8 / Num. measured all: 575464
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.32-1.346.80.52417300.8950.2030.5640.91397.5
1.34-1.356.80.52117710.8660.2030.5620.91298.1
1.35-1.378.30.46917940.9250.1670.4990.89599.2
1.37-1.389.20.45317760.9380.1530.4790.90499.5
1.38-1.49.70.40317610.9570.1330.4250.88999.7
1.4-1.42100.39417980.960.1290.4150.9199.6
1.42-1.4410.40.34517860.9660.110.3630.88799.1
1.44-1.4610.60.30717870.9750.0970.3230.90199.3
1.46-1.4910.50.28417730.9790.0910.2980.89999.2
1.49-1.5110.70.25217620.9840.080.2650.91599.2
1.51-1.5410.50.2317810.9850.0730.2420.94199.4
1.54-1.579.70.217860.9840.0660.2110.94398.8
1.57-1.610.50.18217790.9910.0580.1910.98699.4
1.6-1.6311.70.1717950.9930.0510.1771.00399.7
1.63-1.6611.60.14717800.9940.0440.1531.01999.6
1.66-1.711.60.13218150.9950.040.1381.03399.8
1.7-1.7411.60.1217510.9960.0360.1251.0799.6
1.74-1.7911.60.10418470.9970.0310.1081.04499.5
1.79-1.8411.70.09617390.9970.0290.11.04999.3
1.84-1.911.30.08617850.9970.0270.091.07698.9
1.9-1.9710.10.07517890.9980.0250.0791.09998.6
1.97-2.0511.80.07317640.9980.0220.0761.08299.9
2.05-2.1412.30.06818340.9980.020.0711.08699.9
2.14-2.2612.20.06218200.9990.0180.0651.06899.9
2.26-2.4120.06217830.9980.0180.0641.07299.6
2.4-2.5811.80.05917930.9990.0170.0611.06999.3
2.58-2.8410.40.05418050.9980.0170.0571.04698.6
2.84-3.2612.30.05117960.9990.0150.0531.06899.7
3.26-4.1120.04618340.9990.0140.0481.07799.8
4.1-10011.40.04518640.9990.0140.0471.06899.1

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
PHENIX1.18.2-3874refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2AC0

2ac0


Resolution: 1.32→46.98 Å / SU ML: 0.1232 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 15.4032
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1655 3756 7 %
Rwork0.1404 49917 -
obs0.1422 53673 99.05 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 23.1 Å2
Refinement stepCycle: LAST / Resolution: 1.32→46.98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1508 243 37 294 2082
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00762084
X-RAY DIFFRACTIONf_angle_d1.05672912
X-RAY DIFFRACTIONf_chiral_restr0.0926322
X-RAY DIFFRACTIONf_plane_restr0.0074338
X-RAY DIFFRACTIONf_dihedral_angle_d23.4067847
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.32-1.340.24771200.20541681X-RAY DIFFRACTION90.73
1.34-1.360.28511360.19121852X-RAY DIFFRACTION98.37
1.36-1.370.21461280.16311856X-RAY DIFFRACTION99.3
1.37-1.390.2261430.14581807X-RAY DIFFRACTION99.54
1.39-1.410.17241480.13661886X-RAY DIFFRACTION99.66
1.41-1.440.15241330.12541828X-RAY DIFFRACTION99.19
1.44-1.460.16961360.12061819X-RAY DIFFRACTION99.44
1.46-1.490.1711540.11741852X-RAY DIFFRACTION99.21
1.49-1.510.17251340.10911840X-RAY DIFFRACTION99.2
1.51-1.540.1361350.11311852X-RAY DIFFRACTION99.35
1.54-1.570.1591350.11031813X-RAY DIFFRACTION98.63
1.57-1.610.17021390.10741883X-RAY DIFFRACTION99.75
1.61-1.640.15251350.10711857X-RAY DIFFRACTION99.75
1.64-1.690.15011530.10761850X-RAY DIFFRACTION99.65
1.69-1.730.14961270.11721855X-RAY DIFFRACTION99.75
1.73-1.780.1951500.11751865X-RAY DIFFRACTION99.41
1.78-1.840.16061340.11761842X-RAY DIFFRACTION99.4
1.84-1.910.16791410.11941842X-RAY DIFFRACTION99
1.91-1.980.14251410.1251828X-RAY DIFFRACTION98.65
1.98-2.070.15211460.13121865X-RAY DIFFRACTION99.9
2.07-2.180.14511360.13581861X-RAY DIFFRACTION99.95
2.18-2.320.14641420.13811880X-RAY DIFFRACTION99.8
2.32-2.50.18251400.15091867X-RAY DIFFRACTION99.45
2.5-2.750.20611390.16571859X-RAY DIFFRACTION99.21
2.75-3.150.16511450.16191865X-RAY DIFFRACTION99.01
3.15-3.960.13741430.13991875X-RAY DIFFRACTION99.7
3.96-46.980.1781430.15661937X-RAY DIFFRACTION99.24

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