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- PDB-7b4f: Structural basis of reactivation of oncogenic p53 mutants by a sm... -

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Basic information

Entry
Database: PDB / ID: 7b4f
TitleStructural basis of reactivation of oncogenic p53 mutants by a small molecule: methylene quinuclidinone (MQ). Human p53DBD-R282W mutant bound to DNA: R282W-MQ (I)
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 / TFIID-class transcription factor complex binding / rRNA transcription / 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 / hematopoietic stem cell differentiation / type II interferon-mediated signaling pathway / Pyroptosis / viral process / chromosome organization / 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
FORMIC ACID / 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: 1.78 Å
AuthorsRozenberg, H. / 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

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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)26,3565
Polymers26,1992
Non-polymers1573
Water5,314295
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)52,71310
Polymers52,3984
Non-polymers3156
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_556-x,y,-z+11
Buried area4300 Å2
ΔGint-28 kcal/mol
Surface area22220 Å2
MethodPISA
Unit cell
Length a, b, c (Å)137.210, 49.743, 33.816
Angle α, β, γ (deg.)90.000, 93.357, 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

#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)
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-FMT / FORMIC ACID


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


Mass: 18.015 Da / Num. of mol.: 295 / Source method: isolated from a natural source / Formula: H2O
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: 2.2 Å3/Da / Density % sol: 44.06 % / Mosaicity: 0.698 °
Crystal growTemperature: 292 K / Method: evaporation
Details: Protein/DNA ratio 1:1.5, 0.03M Citric acid, 0.07M BIS-TRIS propane pH=7.6, 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: 1.78→21 Å / Num. obs: 21071 / % possible obs: 95.9 % / Redundancy: 4.8 % / Rmerge(I) obs: 0.067 / Rpim(I) all: 0.034 / Rrim(I) all: 0.076 / Χ2: 1.02 / Net I/σ(I): 11.8 / Num. measured all: 100983
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.78-1.814.60.4529610.8770.2330.5090.83792.3
1.81-1.844.80.40210360.8940.2040.4520.94393.5
1.84-1.884.80.36310320.9090.1830.407192.2
1.88-1.924.80.30710140.9340.1560.3451.03195
1.92-1.964.90.24310160.9560.1220.2721.05693.6
1.96-24.80.2210570.9640.1110.2471.04594
2-2.054.80.1910210.9720.0960.2131.02695.9
2.05-2.114.90.15910220.9790.080.1781.01792.8
2.11-2.174.80.14610630.9820.0730.1641.04497.7
2.17-2.244.90.12710350.9860.0640.1431.02693.9
2.24-2.324.80.11710410.9860.0590.1311.04197.4
2.32-2.424.90.10810730.990.0540.1211.04494.3
2.42-2.524.80.09710600.9910.0490.1091.02499
2.52-2.664.90.09110540.9910.0460.1021.02396
2.66-2.824.80.07610880.9950.0390.0861.03596.6
2.82-3.044.80.06410810.9960.0330.0721.03999.2
3.04-3.354.80.04610910.9980.0230.0521.02798
3.35-3.834.80.03910830.9980.020.0441.04497.9
3.83-4.814.70.03411130.9990.0170.0381.03599.5
4.81-214.60.03111300.9990.0160.0351.04398.8

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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: 1.78→18.42 Å / SU ML: 0.1687 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 18.9604
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1954 2108 10 %
Rwork0.1552 18963 -
obs0.1592 21071 95.72 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 24.56 Å2
Refinement stepCycle: LAST / Resolution: 1.78→18.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1523 206 7 295 2031
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00451917
X-RAY DIFFRACTIONf_angle_d0.72252661
X-RAY DIFFRACTIONf_chiral_restr0.0507289
X-RAY DIFFRACTIONf_plane_restr0.005322
X-RAY DIFFRACTIONf_dihedral_angle_d22.2282744
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.78-1.820.2531170.22711183X-RAY DIFFRACTION89.97
1.82-1.860.2481480.18641213X-RAY DIFFRACTION92.96
1.86-1.910.23831390.18391222X-RAY DIFFRACTION94.19
1.91-1.970.20681310.17961232X-RAY DIFFRACTION93.04
1.97-2.030.23631340.16811246X-RAY DIFFRACTION95.83
2.03-2.110.21231380.16181237X-RAY DIFFRACTION93.16
2.11-2.190.19871440.15991249X-RAY DIFFRACTION97.07
2.19-2.290.18331430.15191268X-RAY DIFFRACTION94.95
2.29-2.410.2071460.16081264X-RAY DIFFRACTION95.33
2.41-2.560.22481320.17071288X-RAY DIFFRACTION98.27
2.56-2.760.23671490.1681296X-RAY DIFFRACTION97.31
2.76-3.040.19151410.16951284X-RAY DIFFRACTION97.47
3.04-3.470.16991520.14531290X-RAY DIFFRACTION97.7
3.47-4.360.17611420.12951326X-RAY DIFFRACTION98.86
4.37-18.420.16261520.13711365X-RAY DIFFRACTION99.54
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)
10.360451841549-0.292866978299-0.08534482704540.5989288789970.3288696887340.162388215605-0.0911117291072-0.03731022398350.1788762847050.155103143290.0238666546382-0.262051643269-0.0543611901112-0.0664551172155-0.008424376032210.15324581853-0.00513977959316-0.006120142784820.1938125020170.04652600560590.24814952923826.8615568443-9.6210749929714.8963522929
20.113045938714-0.0818672856795-0.03295030728920.1478596694150.1127474372550.0760008223799-0.01670223938410.2749089958940.2294602235770.04909486785010.015112346625-0.1103684606210.03365983328160.156687551075-7.05573401062E-50.165025916627-0.0130716874294-0.01914575639020.2135947014740.004956546530970.17579770968417.8182050943-4.340243772849.71793001273
30.1443811994120.0576992993338-0.06528792035720.09639664358880.09067240561210.211099209151-0.06907075033020.4462847940190.0983242947614-0.1985692604140.031273424812-0.155005474438-0.0108762295564-0.05966438396450.06146812755580.140905439851-0.0112809507527-0.004707875281920.1914334543210.08367495351590.29735337221632.9409917156-14.82955999857.33833414737
40.688296296968-0.5796550260350.1174594586260.554939847855-0.2506027838050.325907212565-0.05802477903190.0323726651696-0.08336507761610.0435460618505-0.04182528654670.06369665588230.0611471758297-0.0479380841005-0.002634297321770.159629253488-0.004544258855920.0024801963970.145289302415-0.006722540609440.13027340246914.2815621428-19.033731968315.6380066102
50.800037454324-0.2024869174720.1612762389020.103723914894-0.02512712611670.03691192779830.1523889870610.00318394519451-0.3222638728920.1365750457710.08594687535760.1881470582980.1219036259590.1704155387320.0740533339920.2754320240960.009286091406630.02467001003760.1906521832070.01194030335250.16770133375518.8498029112-27.48770246719.4247454462
60.00879805422979-0.01017206637620.0229658961870.1865257895-0.1463810110050.3629955300640.01491986008280.6588565749460.372333381136-0.2357270440330.0712317825113-0.08689440357020.0280557301313-0.00325429049781-0.03894505925630.2125249688550.01733911027860.0835405898470.3577884164420.1245713940390.24289971677330.2506685275-18.29198992364.56713369607
70.28301499962-0.1331682227130.1601623646940.737557447737-0.04624586409520.334945686772-0.03079445701360.07995232430530.05858423087610.0506652214224-0.0257062144016-0.0961891722248-0.0163023767896-0.00185798466806-1.43980973009E-50.1535841892750.00375579748345-0.001040415386740.1474405901760.006075547771240.14872072039619.0507277995-13.219822904714.7281092467
80.241789712499-0.0502286782462-0.2825417029640.06944478815250.1532779783330.4713542706160.0120738776740.01432283980340.234835169257-0.1492756064280.06110877336550.059914541609-0.1532969857030.1119522931430.06981492710850.173781259860.0112469403099-0.005523409947170.1494343638460.02559032783330.23747104855215.19420955056.6094515204515.1873708194
90.2026935891750.104717386621-0.1197931302640.1997425320260.1264886558940.2819199213040.04180131779750.01334355131850.117033597133-0.05572088076810.1043701776290.0611900784477-0.1572619822310.02191135197490.01418889737790.214478567739-0.00544862008556-0.01094674762190.207043123699-0.01670396809240.179723432165-0.5107346914453.5087828337913.883213601
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 123 )AA94 - 1231 - 33
22chain 'A' and (resid 124 through 140 )AA124 - 14034 - 52
33chain 'A' and (resid 141 through 155 )AA141 - 15553 - 68
44chain 'A' and (resid 156 through 203 )AA156 - 20369 - 117
55chain 'A' and (resid 204 through 213 )AA204 - 213118 - 128
66chain 'A' and (resid 214 through 229 )AA214 - 229129 - 147
77chain 'A' and (resid 230 through 277 )AA230 - 277148 - 196
88chain 'A' and (resid 278 through 293 )AA278 - 293197 - 214
99chain 'B' and (resid 1 through 11 )BC1 - 11

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