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Yorodumi- PDB-7b4d: Structural basis of reactivation of oncogenic p53 mutants by a sm... -
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-Basic information
Entry | Database: PDB / ID: 7b4d | ||||||
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Title | Structural basis of reactivation of oncogenic p53 mutants by a small molecule: methylene quinuclidinone (MQ). Human p53DBD-R273C/S240R double mutant bound to DNA and MQ: R273C/S240R-DNA-MQ | ||||||
Components |
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Keywords | TRANSCRIPTION / 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 / 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 / Activation of NOXA and translocation to mitochondria / 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 / 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 / Activation of NOXA and translocation to mitochondria / negative regulation of pentose-phosphate shunt / ATP-dependent DNA/DNA annealing activity / negative regulation of helicase activity / regulation of cell cycle G2/M phase transition / intrinsic apoptotic signaling pathway in response to hypoxia / regulation of fibroblast apoptotic process / oxidative stress-induced premature senescence / oligodendrocyte apoptotic process / negative regulation of miRNA processing / positive regulation of thymocyte apoptotic process / glucose catabolic process to lactate via pyruvate / regulation of tissue remodeling / positive regulation of mitochondrial membrane permeability / negative regulation of mitophagy / positive regulation of programmed necrotic cell death / mRNA transcription / bone marrow development / circadian behavior / histone deacetylase regulator activity / T cell proliferation involved in immune response / regulation of mitochondrial membrane permeability involved in apoptotic process / RUNX3 regulates CDKN1A transcription / germ cell nucleus / regulation of DNA damage response, signal transduction by p53 class mediator / 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 / negative regulation of neuroblast proliferation / DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / negative regulation of glial cell proliferation / Regulation of TP53 Activity through Association with Co-factors / positive regulation of execution phase of apoptosis / mitochondrial DNA repair / T cell lineage commitment / negative regulation of DNA replication / ER overload response / B cell lineage commitment / thymocyte apoptotic process / positive regulation of cardiac muscle cell apoptotic process / TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain / TP53 Regulates Transcription of Caspase Activators and Caspases / entrainment of circadian clock by photoperiod / cardiac septum morphogenesis / PI5P Regulates TP53 Acetylation / Association of TriC/CCT with target proteins during biosynthesis / Zygotic genome activation (ZGA) / necroptotic process / negative regulation of telomere maintenance via telomerase / positive regulation of release of cytochrome c from mitochondria / rRNA transcription / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / TFIID-class transcription factor complex binding / mitophagy / SUMOylation of transcription factors / intrinsic apoptotic signaling pathway by p53 class mediator / neuroblast proliferation / general transcription initiation factor binding / cellular response to actinomycin D / Transcriptional Regulation by VENTX / response to X-ray / DNA damage response, signal transduction by p53 class mediator / replicative senescence / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / chromosome organization / gastrulation / cellular response to UV-C / response to inorganic substance / hematopoietic stem cell differentiation / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / negative regulation of reactive oxygen species metabolic process / positive regulation of RNA polymerase II transcription preinitiation complex assembly / MDM2/MDM4 family protein binding / glial cell proliferation / embryonic organ development / cellular response to glucose starvation / Pyroptosis / cis-regulatory region sequence-specific DNA binding / hematopoietic progenitor cell differentiation / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / somitogenesis / type II interferon-mediated signaling pathway / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / positive regulation of intrinsic apoptotic signaling pathway / negative regulation of fibroblast proliferation / negative regulation of stem cell proliferation / core promoter sequence-specific DNA binding / cardiac muscle cell apoptotic process / response to salt stress / transcription initiation-coupled chromatin remodeling / mitotic G1 DNA damage checkpoint signaling / Regulation of TP53 Activity through Acetylation Similarity search - Function | ||||||
Biological species | Homo sapiens (human) synthetic construct (others) | ||||||
Method | X-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.85 Å | ||||||
Authors | Rozenberg, H. / Diskin-Posner, Y. / Degtjarik, O. / Shakked, Z. | ||||||
Funding support | 1items
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 7b4d.cif.gz | 141.6 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7b4d.ent.gz | 88.6 KB | Display | PDB format |
PDBx/mmJSON format | 7b4d.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/b4/7b4d ftp://data.pdbj.org/pub/pdb/validation_reports/b4/7b4d | HTTPS FTP |
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-Related structure data
Related structure data | 6zncC 7b46C 7b47C 7b48C 7b49C 7b4aC 7b4bC 7b4cC 7b4eC 7b4fC 7b4gC 7b4hC 7b4nC 2ac0S C: citing same article (ref.) S: Starting model for refinement |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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Unit cell |
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-Components
-Protein / DNA chain , 2 types, 2 molecules AC
#1: Protein | Mass: 22521.646 Da / Num. of mol.: 1 / Fragment: p53 human DNA binding domain / Mutation: R273C S240R 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 |
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#2: DNA chain | 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) |
-Non-polymers , 5 types, 156 molecules
#3: Chemical | ChemComp-ZN / | ||||||
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#4: Chemical | #5: Chemical | ChemComp-QN8 / ( | #6: Chemical | #7: Water | ChemComp-HOH / | |
-Details
Has ligand of interest | Y |
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Nonpolymer details | Two 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
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.25 Å3/Da / Density % sol: 45.41 % / Mosaicity: 0.557 ° |
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Crystal grow | Temperature: 292 K / Method: evaporation / pH: 6.1 Details: Protein/DNA ratio 1:2.4, 0.2M Sodium formate, 20% w/v PEG 3350 |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Diffraction source | Source: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54178 Å | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Detector | Type: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Oct 10, 2015 / Details: mirrors | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Radiation | Monochromator: VariMax Optics / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Radiation wavelength | Wavelength: 1.54178 Å / Relative weight: 1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reflection | Resolution: 1.85→25 Å / Num. obs: 19150 / % possible obs: 95.6 % / Redundancy: 9.5 % / Rmerge(I) obs: 0.057 / Rpim(I) all: 0.019 / Rrim(I) all: 0.061 / Χ2: 1.013 / Net I/σ(I): 12.9 / Num. measured all: 181291 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reflection shell | Diffraction-ID: 1
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-Phasing
Phasing | Method: molecular replacement |
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-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 2AC0 Resolution: 1.85→18.28 Å / SU ML: 0.191 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 20.9373 Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
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Solvent computation | Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 38.78 Å2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 1.85→18.28 Å
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Refine LS restraints |
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LS refinement shell |
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Refinement TLS params. | Method: refined / Refine-ID: X-RAY DIFFRACTION
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Refinement TLS group | Refine-ID: X-RAY DIFFRACTION
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