[English] 日本語
Yorodumi
- PDB-7b4e: Structural basis of reactivation of oncogenic p53 mutants by a sm... -

+
Open data


ID or keywords:

Loading...

-
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


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 / Activation of NOXA and translocation to mitochondria ...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 / Activation of NOXA and translocation to mitochondria / ATP-dependent DNA/DNA annealing activity / 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 / germ cell nucleus / regulation of fibroblast apoptotic process / bone marrow development / circadian behavior / histone deacetylase regulator activity / positive regulation of programmed necrotic cell death / cellular response to actinomycin D / : / regulation of mitochondrial membrane permeability involved in apoptotic process / RUNX3 regulates CDKN1A transcription / T cell proliferation involved in immune response / 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 / mRNA transcription / negative regulation of glial cell proliferation / regulation of DNA damage response, signal transduction by p53 class mediator / Regulation of TP53 Activity through Association with Co-factors / 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) / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / PI5P Regulates TP53 Acetylation / necroptotic process / negative regulation of telomere maintenance via telomerase / Association of TriC/CCT with target proteins during biosynthesis / 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 / rRNA transcription / negative regulation of reactive oxygen species metabolic process / TFIID-class transcription factor complex binding / Transcriptional Regulation by VENTX / intrinsic apoptotic signaling pathway by p53 class mediator / cellular response to UV-C / viral process / neuroblast proliferation / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / replicative senescence / positive regulation of RNA polymerase II transcription preinitiation complex assembly / Pyroptosis / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / general transcription initiation factor binding / chromosome organization / positive regulation of execution phase of apoptosis / hematopoietic stem cell differentiation / type II interferon-mediated signaling pathway / embryonic organ development / 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 / negative regulation of fibroblast proliferation / cellular response to glucose starvation / mitophagy / cis-regulatory region sequence-specific DNA binding / Regulation of TP53 Activity through Acetylation / negative regulation of proteolysis / mitotic G1 DNA damage checkpoint signaling / positive regulation of intrinsic apoptotic signaling pathway / response to salt stress / cardiac muscle cell apoptotic process / transcription repressor complex / 14-3-3 protein binding / gastrulation / positive regulation of cardiac muscle cell apoptotic process / transforming growth factor beta receptor signaling pathway / MDM2/MDM4 family protein binding
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
(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

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
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

-
Components

-
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)

-
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

-
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.

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
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

-
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

-
Phasing

PhasingMethod: molecular replacement

-
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

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more