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- PDB-7b4e: Structural basis of reactivation of oncogenic p53 mutants by a sm... -

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Basic information

Entry
Database: PDB / ID: 7b4e
TitleStructural basis of reactivation of oncogenic p53 mutants by a small molecule: methylene quinuclidinone (MQ). Human p53DBD-R282W mutant bound to DNA and MQ: R282W-DNA-MQ
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


Loss of function of TP53 in cancer due to loss of tetramerization ability / Regulation of TP53 Expression / negative regulation of helicase activity / 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 ...Loss of function of TP53 in cancer due to loss of tetramerization ability / Regulation of TP53 Expression / negative regulation of helicase activity / 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 / regulation of fibroblast apoptotic process / intrinsic apoptotic signaling pathway in response to hypoxia / oligodendrocyte apoptotic process / negative regulation of miRNA processing / positive regulation of thymocyte apoptotic process / oxidative stress-induced premature senescence / regulation of tissue remodeling / glucose catabolic process to lactate via pyruvate / positive regulation of mitochondrial membrane permeability / positive regulation of programmed necrotic cell death / mRNA transcription / bone marrow development / circadian behavior / regulation of mitochondrial membrane permeability involved in apoptotic process / germ cell nucleus / RUNX3 regulates CDKN1A transcription / TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain / TP53 Regulates Transcription of Death Receptors and Ligands / Activation of PUMA and translocation to mitochondria / 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 / T cell lineage commitment / mitochondrial DNA repair / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / ER overload response / B cell lineage commitment / thymocyte apoptotic process / TP53 Regulates Transcription of Caspase Activators and Caspases / negative regulation of mitophagy / cardiac septum morphogenesis / negative regulation of DNA replication / entrainment of circadian clock by photoperiod / PI5P Regulates TP53 Acetylation / negative regulation of telomere maintenance via telomerase / Zygotic genome activation (ZGA) / positive regulation of release of cytochrome c from mitochondria / Association of TriC/CCT with target proteins during biosynthesis / necroptotic process / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / rRNA transcription / 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 / T cell proliferation involved in immune response / negative regulation of reactive oxygen species metabolic process / positive regulation of execution phase of apoptosis / Transcriptional Regulation by VENTX / replicative senescence / cellular response to UV-C / general transcription initiation factor binding / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / cellular response to actinomycin D / neuroblast proliferation / positive regulation of RNA polymerase II transcription preinitiation complex assembly / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / response to X-ray / type II interferon-mediated signaling pathway / hematopoietic stem cell differentiation / Pyroptosis / chromosome organization / viral process / embryonic organ development / somitogenesis / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / glial cell proliferation / hematopoietic progenitor cell differentiation / core promoter sequence-specific DNA binding / negative regulation of stem cell proliferation / cellular response to glucose starvation / cis-regulatory region sequence-specific DNA binding / mitophagy / negative regulation of fibroblast proliferation / positive regulation of cardiac muscle cell apoptotic process / positive regulation of intrinsic apoptotic signaling pathway / tumor necrosis factor-mediated signaling pathway / negative regulation of proteolysis / Regulation of TP53 Activity through Acetylation / mitotic G1 DNA damage checkpoint signaling / gastrulation / 14-3-3 protein binding / response to salt stress / MDM2/MDM4 family protein binding / cardiac muscle cell apoptotic process / transcription repressor complex
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
(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: 1.58 Å
AuthorsDegtjarik, O. / Rozenberg, H. / Shakked, Z.
Funding support Sweden, 1items
OrganizationGrant numberCountry
Aprea Therapeutics AB Sweden
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 1.3Nov 13, 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)26,81010
Polymers25,8702
Non-polymers9418
Water4,936274
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)53,62120
Polymers51,7404
Non-polymers1,88116
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_556-x,y,-z+11
Buried area5640 Å2
ΔGint-7 kcal/mol
Surface area21990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)136.505, 49.553, 33.401
Angle α, β, γ (deg.)90.000, 93.443, 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
11A-306-

PG4

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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: 3335.174 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 , 6 types, 282 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.: 3 / 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-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#7: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 274 / 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: 2.17 Å3/Da / Density % sol: 43.38 % / Mosaicity: 0.371 °
Crystal growTemperature: 292 K / Method: evaporation / pH: 6.1
Details: Protein/DNA ratio 1:1.5, 0.1M Sodium Acetate, 20% w/v PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-3 / Wavelength: 0.9677 Å
DetectorType: DECTRIS EIGER X 4M / Detector: PIXEL / Date: Aug 7, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9677 Å / Relative weight: 1
ReflectionResolution: 1.57→50 Å / Num. obs: 30188 / % possible obs: 97.5 % / Redundancy: 10.1 % / Rmerge(I) obs: 0.111 / Rpim(I) all: 0.034 / Rrim(I) all: 0.116 / Χ2: 0.954 / Net I/σ(I): 6.3
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.58-1.614.40.6114430.7160.3040.6850.67693.5
1.61-1.645.80.55614490.8010.2370.6070.61596
1.64-1.676.50.51415320.8430.2040.5540.6297.3
1.67-1.77.70.44614850.910.1630.4760.65397.8
1.7-1.748.50.42815070.9190.1490.4540.69298.4
1.74-1.789.30.37715460.950.1260.3990.71298.6
1.78-1.82100.33614920.9630.1090.3530.75898.7
1.82-1.8710.50.30615250.9670.0960.3210.79598.3
1.87-1.9310.80.26814940.9790.0830.280.91398.7
1.93-1.9911.20.24215620.9830.0740.2531.0499
1.99-2.0611.50.21515050.9830.0650.2251.08598.7
2.06-2.1411.50.18815170.990.0570.1971.06798.4
2.14-2.2411.50.16915320.990.0510.1761.06398.3
2.24-2.3610.90.15214800.990.0480.1591.07596.9
2.36-2.5110.50.1413320.9880.0450.1471.09685.9
2.51-2.712.10.12414940.9950.0370.131.10496.4
2.7-2.9712.80.10615490.9960.0310.1111.08799.9
2.97-3.412.60.08115750.9980.0240.0851.087100
3.4-4.2912.30.06915640.9980.020.0721.076100
4.29-5011.90.05916050.9980.0180.0621.01799.8

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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: 1.58→34.06 Å / SU ML: 0.1919 / Cross valid method: FREE R-VALUE / σ(F): 1.4 / Phase error: 18.2649
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2013 2009 6.66 %
Rwork0.1662 28173 -
obs0.1684 30182 97.21 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 21.77 Å2
Refinement stepCycle: LAST / Resolution: 1.58→34.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1491 206 62 274 2033
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00582122
X-RAY DIFFRACTIONf_angle_d1.05032956
X-RAY DIFFRACTIONf_chiral_restr0.0564319
X-RAY DIFFRACTIONf_plane_restr0.0047346
X-RAY DIFFRACTIONf_dihedral_angle_d26.5056845
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.57-1.610.29721200.29051849X-RAY DIFFRACTION89.79
1.61-1.660.29951470.23392008X-RAY DIFFRACTION96.85
1.66-1.70.22581420.20721987X-RAY DIFFRACTION97.8
1.7-1.760.18661460.18482041X-RAY DIFFRACTION98.42
1.76-1.820.20981410.17052015X-RAY DIFFRACTION98.63
1.82-1.90.19271500.17232023X-RAY DIFFRACTION98.5
1.9-1.980.22671410.17192077X-RAY DIFFRACTION98.8
1.98-2.090.19821460.17192021X-RAY DIFFRACTION98.77
2.09-2.220.18491440.16292023X-RAY DIFFRACTION98.37
2.22-2.390.19241450.16872021X-RAY DIFFRACTION96.96
2.39-2.630.19421300.16381813X-RAY DIFFRACTION88.2
2.63-3.010.19621540.16862080X-RAY DIFFRACTION99.91
3.01-3.790.20191470.14412086X-RAY DIFFRACTION100
3.79-34.060.18651560.14792129X-RAY DIFFRACTION99.74
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)
11.08464587076-0.219445315694-0.2442622454291.078435043170.2291308621390.141049888579-0.0526712707620.005644008599010.147269313603-0.0260725140906-0.000560115113173-0.102540617941-0.0003743450210250.008808056508530.02255875189280.123534065623-0.00758546037518-0.02118196851970.1244770386860.01973390451450.15186179116725.4839195967-9.7688809068414.6163081031
21.33180654519-0.190217940690.3216692397160.8518661893240.05955735994350.50663002609-0.06460071034980.05306744073180.05603988784450.0298519585256-0.026112388643-0.0359426065642-0.0353311095118-0.06328413048890.07714305366630.1194563533380.00465068844576-0.007198727768880.08452620489740.006715153459150.10461362139520.6571721806-16.28692714914.8987384363
33.77106588937-0.849112298778-0.5485518041961.75487869192-0.0842749939850.1584971427520.01635515078280.25622250793-0.552828003048-0.0771743197431-0.07359971940250.2332093541330.147773552762-0.2741461167970.0714063123210.115875610322-0.00391699817608-0.007617216381920.1439116107-0.03452125055090.1753399226696.64227111342-23.584760833110.9590305399
40.979728637124-0.02252204118450.07851339736151.41731047366-0.01260936899421.902473114610.08427739337080.0918404185598-0.13973097474-0.009107679612330.05119642058770.07053902528250.2150191508190.03631116455320.02328847359850.1358880245650.01045170079890.004584798206940.113562760672-0.01405788400940.081949422916919.2144431371-26.840713320612.02996564
51.03833978309-0.3068183607560.3784313027151.25901218994-0.03334289138860.571808501414-0.03048100101710.1285133329290.0877404075787-0.0597647386855-0.0168768728421-0.0709241841758-0.008072081729950.003151748399440.01909274279030.105177341722-0.001151759788310.006321932211060.1103390085150.01398607444440.089067834895322.2738566977-15.776824161811.4971646002
62.145919524631.6209010112.096493636752.057318929621.722419649122.84423313633-0.1163602034060.09764069409510.336343238592-0.1548275008770.06240605362620.0897193094774-0.1756819544750.2284656460580.014911600960.1688116967550.003371051627560.0006219941176120.1682311716910.03148562645830.25652970055315.37926643135.6912476503315.1253750003
71.97001215253-0.139419035608-0.2763012935772.580142044590.1278434577813.353716529080.2201301116490.3195238533350.130435845441-0.3429913897750.003393988423960.143483462399-0.2463943029680.329323710144-0.1549340992830.266251131744-0.0152204089689-0.01813383607740.258452207644-0.01274920623220.211284137343-1.854446632752.4652172025713.8684422685
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 94 through 135 )AA94 - 1351 - 40
22chain 'A' and (resid 136 through 176 )AA136 - 17641 - 88
33chain 'A' and (resid 177 through 194 )AA177 - 19489 - 104
44chain 'A' and (resid 195 through 213 )AA195 - 213105 - 128
55chain 'A' and (resid 214 through 277 )AA214 - 277129 - 199
66chain 'A' and (resid 278 through 293 )AA278 - 293200 - 220
77chain 'B' and (resid 1 through 11 )BI1 - 11

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