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- PDB-7b4g: Structural basis of reactivation of oncogenic p53 mutants by a sm... -

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Basic information

Entry
Database: PDB / ID: 7b4g
TitleStructural basis of reactivation of oncogenic p53 mutants by a small molecule: methylene quinuclidinone (MQ). Human p53DBD-R282W mutant bound to DNA: R282W-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 / regulation of fibroblast apoptotic process / positive regulation of thymocyte apoptotic process / oxidative stress-induced premature senescence / regulation of tissue remodeling / positive regulation of mitochondrial membrane permeability / mRNA transcription / bone marrow development / positive regulation of programmed necrotic cell death / circadian behavior / T cell proliferation involved in immune response / regulation of mitochondrial membrane permeability involved in apoptotic process / germ cell nucleus / RUNX3 regulates CDKN1A transcription / homolactic fermentation / TP53 Regulates Transcription of Death Receptors and Ligands / Activation of PUMA and translocation to mitochondria / TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain / regulation of DNA damage response, signal transduction by p53 class mediator / histone deacetylase regulator activity / negative regulation of glial cell proliferation / Regulation of TP53 Activity through Association with Co-factors / negative regulation of neuroblast proliferation / mitochondrial DNA repair / T cell lineage commitment / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / ER overload response / thymocyte apoptotic process / B cell lineage commitment / TP53 Regulates Transcription of Caspase Activators and Caspases / entrainment of circadian clock by photoperiod / cardiac septum morphogenesis / negative regulation of mitophagy / negative regulation of DNA replication / Zygotic genome activation (ZGA) / positive regulation of release of cytochrome c from mitochondria / PI5P Regulates TP53 Acetylation / Association of TriC/CCT with target proteins during biosynthesis / necroptotic process / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / negative regulation of telomere maintenance via telomerase / TFIID-class transcription factor complex binding / SUMOylation of transcription factors / TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain / intrinsic apoptotic signaling pathway by p53 class mediator / rRNA transcription / negative regulation of reactive oxygen species metabolic process / Transcriptional Regulation by VENTX / cellular response to UV-C / replicative senescence / general transcription initiation factor binding / cellular response to actinomycin D / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / positive regulation of RNA polymerase II transcription preinitiation complex assembly / neuroblast proliferation / viral process / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / positive regulation of execution phase of apoptosis / Pyroptosis / hematopoietic stem cell differentiation / response to X-ray / embryonic organ development / chromosome organization / type II interferon-mediated signaling pathway / somitogenesis / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / hematopoietic progenitor cell differentiation / glial cell proliferation / negative regulation of fibroblast proliferation / positive regulation of cardiac muscle cell apoptotic process / core promoter sequence-specific DNA binding / negative regulation of stem cell proliferation / cellular response to glucose starvation / mitophagy / cis-regulatory region sequence-specific DNA binding / positive regulation of intrinsic apoptotic signaling pathway / Regulation of TP53 Activity through Acetylation / gastrulation / response to salt stress / 14-3-3 protein binding / mitotic G1 DNA damage checkpoint signaling / negative regulation of proteolysis / cardiac muscle cell apoptotic process / MDM2/MDM4 family protein binding / transcription repressor complex / intrinsic apoptotic 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 / p53 tumour suppressor family ...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
DI(HYDROXYETHYL)ETHER / DNA / DNA (> 10) / Cellular tumor antigen p53
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.86 Å
AuthorsDegtjarik, O. / Rozenberg, H. / 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)26,6198
Polymers26,1992
Non-polymers4206
Water5,729318
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)53,23816
Polymers52,3984
Non-polymers84012
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_758-x+2,y,-z+31
Buried area5650 Å2
ΔGint-7 kcal/mol
Surface area22990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)137.439, 49.859, 34.050
Angle α, β, γ (deg.)90.000, 93.711, 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
Components on special symmetry positions
IDModelComponents
11B-156-

HOH

21B-163-

HOH

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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: 22534.598 Da / Num. of mol.: 1 / Fragment: p53 human DNA binding domain / Mutation: R282W
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 , 4 types, 324 molecules

#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


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


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 318 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN

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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: 2.22 Å3/Da / Density % sol: 44.55 % / Mosaicity: 0.675 °
Crystal growTemperature: 292 K / Method: evaporation
Details: Protein/DNA ratio 1:1.5, 0.2M Sodium Acetate, 20% w/v PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54178 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Mar 10, 2009
RadiationMonochromator: VariMax Optics / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.86→40 Å / Num. obs: 18811 / % possible obs: 96.2 % / Redundancy: 3.5 % / Rmerge(I) obs: 0.088 / Rpim(I) all: 0.055 / Rrim(I) all: 0.104 / Χ2: 0.91 / Net I/σ(I): 7.7 / Num. measured all: 66152
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.86-1.893.40.4829220.8180.30.5690.72191.9
1.89-1.933.50.429150.8340.2590.4940.71994.8
1.93-1.963.50.3339000.8830.2060.3930.76293.9
1.96-23.50.3099110.910.1910.3640.7492.9
2-2.053.50.2669070.9210.1650.3140.78396.2
2.05-2.093.60.2239160.9490.1370.2620.78493.9
2.09-2.153.50.2129360.9450.1310.2490.86295
2.15-2.213.50.1829180.9620.1130.2150.81696.6
2.21-2.273.50.1669370.9660.1020.1950.86793.2
2.27-2.343.50.1569450.9660.0970.1840.95399.1
2.34-2.433.60.159200.9710.0930.1760.91293.6
2.43-2.523.50.1379510.9760.0850.1610.95999
2.52-2.643.60.1229480.980.0760.1440.97494.7
2.64-2.783.50.1049490.9850.0640.1221.00399.3
2.78-2.953.60.099400.9890.0560.1071.11796.8
2.95-3.183.50.0689630.9930.0420.0811.0897.4
3.18-3.53.50.0559610.9960.0340.0651.05298.4
3.5-4.013.50.0459660.9960.0290.0531.02898.6
4.01-5.053.50.0419910.9970.0260.0491.01399
5.05-403.40.04510150.9980.0290.0541.01399.1

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Phasing

PhasingMethod: molecular replacement

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Processing

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

2ac0


Resolution: 1.86→34.29 Å / SU ML: 0.1977 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 19.6241
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2051 1897 10.08 %
Rwork0.147 16914 -
obs0.1528 18811 96.06 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 21.67 Å2
Refinement stepCycle: LAST / Resolution: 1.86→34.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1550 226 24 318 2118
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072033
X-RAY DIFFRACTIONf_angle_d0.94832817
X-RAY DIFFRACTIONf_chiral_restr0.0617299
X-RAY DIFFRACTIONf_plane_restr0.0061340
X-RAY DIFFRACTIONf_dihedral_angle_d22.5964797
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.86-1.90.29511260.22731160X-RAY DIFFRACTION91.66
1.9-1.960.26411390.1711165X-RAY DIFFRACTION94.15
1.96-2.010.23491310.17711194X-RAY DIFFRACTION93.71
2.01-2.080.23071170.16871182X-RAY DIFFRACTION95.23
2.08-2.150.22041500.14721183X-RAY DIFFRACTION95.01
2.15-2.240.20271290.14551171X-RAY DIFFRACTION95.17
2.24-2.340.22211370.14651214X-RAY DIFFRACTION96.98
2.34-2.460.23431330.15211191X-RAY DIFFRACTION94.98
2.46-2.620.20151360.14631219X-RAY DIFFRACTION96.24
2.62-2.820.23531370.15471218X-RAY DIFFRACTION97.83
2.82-3.10.21681360.15461226X-RAY DIFFRACTION97.36
3.1-3.550.17291370.13511247X-RAY DIFFRACTION98.86
3.55-4.470.17721410.12291246X-RAY DIFFRACTION98.65
4.48-34.290.17391480.14011298X-RAY DIFFRACTION99.11
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)
10.593191329397-0.3758742731540.09880227572060.7621828359210.086512241180.138438352240.005974684166240.08723204847680.0415735768035-0.0244959315988-0.0394528005837-0.04926067717070.0227528149340.00626081581105-0.004366775383030.09745470661780.01420517993170.01011401493350.0985652791610.01707837176360.0820883762398155.398084003-15.508941509446.9277563076
20.1598705477450.0327795139359-0.161098310280.2974575721110.08755651014270.18497777970.0454259192142-0.1082445213540.1232233971810.09479843929620.01793659508940.0786771240971-0.186930256664-0.01948895338450.005407328003660.177690929898-0.00592170356622-0.01078118881120.1468649617-0.02944714330510.147388875994135.4179917310.031552471819649.5999354197
30.303778632027-0.1996873060760.05166583674690.3510327035580.07466758333630.0111792207222-0.07919932153770.0144930768020.1017828713030.08296739174860.0245888573002-0.150832976481-0.0487013819477-0.0406842064655-0.01090345157180.100475177661-0.0103136368482-0.003195156550890.1408666334960.02609488359120.136257305178160.596208601-10.280763683547.5380126634
40.543594922028-0.1088217891020.1662497805390.3697134072790.01173900948040.024258926118-0.05026750149680.02208497173510.05393301780130.0635435986763-0.040163319515-0.061887391512-0.026077737408-0.0031124768936-0.03786540390220.09205480515950.00592117928699-0.008734013476660.09316039990040.01635811410610.100370724179155.605286313-16.549221620448.9462609315
50.300227161730.0760519222375-0.03670232021040.06883193421770.0262935870080.0295153410664-0.06610801696020.228837899591-0.42656253173-0.0267375307287-0.07119710076590.0624247967948-0.0233563244538-0.237316288997-0.01770805650670.153994165742-0.008672546373680.01050963271540.182783683333-0.04346371125690.170855403539141.126794227-24.893307000145.2007122488
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 195 through 293 )AA195 - 293110 - 217
22chain 'B' and (resid 1 through 12 )BH1 - 12
33chain 'A' and (resid 94 through 131 )AA94 - 1311 - 39
44chain 'A' and (resid 132 through 176 )AA132 - 17640 - 92
55chain 'A' and (resid 177 through 194 )AA177 - 19493 - 109

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