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- PDB-5a7b: Structure of the p53 cancer Y220C bound to the stabilizing small ... -

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Basic information

Entry
Database: PDB / ID: 5a7b
TitleStructure of the p53 cancer Y220C bound to the stabilizing small molecule PhiKan5211
ComponentsCELLULAR TUMOR ANTIGEN P53
KeywordsANTITUMOR PROTEIN / CANCER / TUMOR SUPPRESSION / ETHYNYL / DNA BINDING / CANCER THERAPY / SMALL MOLECULE STABILIZERS / MOLECULAR CHAPERONE
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 / regulation of tissue remodeling / glucose catabolic process to lactate via pyruvate / 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 / germ cell nucleus / T cell lineage commitment / regulation of mitochondrial membrane permeability involved in apoptotic process / RUNX3 regulates CDKN1A transcription / 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 / DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / B cell lineage commitment / thymocyte apoptotic process / negative regulation of glial cell proliferation / negative regulation of neuroblast proliferation / Regulation of TP53 Activity through Association with Co-factors / mitochondrial DNA repair / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / TP53 Regulates Transcription of Caspase Activators and Caspases / ER overload response / positive regulation of release of cytochrome c from mitochondria / negative regulation of DNA replication / 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 / entrainment of circadian clock by photoperiod / cardiac septum morphogenesis / PI5P Regulates TP53 Acetylation / Association of TriC/CCT with target proteins during biosynthesis / necroptotic process / Zygotic genome activation (ZGA) / positive regulation of execution phase of apoptosis / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / TFIID-class transcription factor complex binding / rRNA transcription / negative regulation of telomere maintenance via telomerase / SUMOylation of transcription factors / intrinsic apoptotic signaling pathway by p53 class mediator / general transcription initiation factor binding / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / Transcriptional Regulation by VENTX / DNA damage response, signal transduction by p53 class mediator / response to X-ray / replicative senescence / Pyroptosis / mitophagy / cellular response to UV-C / positive regulation of RNA polymerase II transcription preinitiation complex assembly / neuroblast proliferation / hematopoietic stem cell differentiation / negative regulation of reactive oxygen species metabolic process / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / somitogenesis / embryonic organ development / chromosome organization / T cell proliferation involved in immune response / type II interferon-mediated signaling pathway / glial cell proliferation / viral process / cis-regulatory region sequence-specific DNA binding / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / hematopoietic progenitor cell differentiation / cellular response to actinomycin D / positive regulation of intrinsic apoptotic signaling pathway / cellular response to glucose starvation / core promoter sequence-specific DNA binding / negative regulation of stem cell proliferation / mitotic G1 DNA damage checkpoint signaling / negative regulation of fibroblast proliferation / gastrulation / MDM2/MDM4 family protein binding / tumor necrosis factor-mediated signaling pathway / response to salt stress / cardiac muscle cell apoptotic process / 14-3-3 protein binding / Regulation of TP53 Activity through Acetylation
Similarity search - Function
Immunoglobulin-like - #720 / 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 ...Immunoglobulin-like - #720 / 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 / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Chem-KMN / Cellular tumor antigen p53
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.4 Å
AuthorsJoerger, A.C.
CitationJournal: Acs Chem.Biol. / Year: 2015
Title: Experimental and Theoretical Evaluation of the Ethynyl Moiety as a Halogen Bioisostere.
Authors: Wilcken, R. / Zimmermann, M.O. / Bauer, M.R. / Rutherford, T.J. / Fersht, A.R. / Joerger, A.C. / Boeckler, F.M.
History
DepositionJul 3, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 30, 2015Provider: repository / Type: Initial release
Revision 1.1Jan 13, 2016Group: Database references
Revision 1.2May 8, 2019Group: Data collection / Experimental preparation / Other
Category: exptl_crystal_grow / pdbx_database_proc / pdbx_database_status
Item: _exptl_crystal_grow.temp / _pdbx_database_status.recvd_author_approval
Revision 1.3May 15, 2019Group: Data collection / Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.method
Revision 1.4Jan 10, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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: CELLULAR TUMOR ANTIGEN P53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,0266
Polymers49,0622
Non-polymers9644
Water11,115617
1
A: CELLULAR TUMOR ANTIGEN P53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,0133
Polymers24,5311
Non-polymers4822
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: CELLULAR TUMOR ANTIGEN P53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,0133
Polymers24,5311
Non-polymers4822
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)65.120, 71.111, 105.114
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein CELLULAR TUMOR ANTIGEN P53 / ANTIGEN NY-CO-13 / PHOSPHOPROTEIN P53 / TUMOR SUPPRESSOR P53


Mass: 24530.811 Da / Num. of mol.: 2 / Fragment: DNA-BINDING DOMAIN, UNP RESIDUES 94-312 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P04637
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-KMN / 2-[[4-(diethylamino)piperidin-1-yl]methyl]-6-ethynyl-4-(3-phenoxyprop-1-ynyl)phenol


Mass: 416.555 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H32N2O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 617 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.5 Å3/Da / Density % sol: 51 % / Description: NONE
Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop
Details: CRYSTALLIZATION CONDITIONS: SITTING-DROP VAPOR DIFFUSION AT 21 DEGREE C. PROTEIN SOLUTION: 6 MG/ML PROTEIN IN 25 MM SODIUM PHOSPHATE, PH 7.2, 150 MM KCL, 5 MM DTT. RESERVOIR BUFFER: 100 MM ...Details: CRYSTALLIZATION CONDITIONS: SITTING-DROP VAPOR DIFFUSION AT 21 DEGREE C. PROTEIN SOLUTION: 6 MG/ML PROTEIN IN 25 MM SODIUM PHOSPHATE, PH 7.2, 150 MM KCL, 5 MM DTT. RESERVOIR BUFFER: 100 MM HEPES, PH 7.2, 19% (W/V) POLYETHYLENE GLYCOL 4000, 5 MM DTT. SOAKING BUFFER: 30 MM COMPOUND IN 100 MM HEPES, PH 7.2, 10 MM SODIUM PHOSPHATE, PH 7.2, 19% (W/V) POLYETHYLENE GLYCOL 4000, 20 % (V/V) GLYCEROL, 150 MM KCL.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9763
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 1.4→29.6 Å / Num. obs: 94496 / % possible obs: 99.9 % / Observed criterion σ(I): 2 / Redundancy: 5.3 % / Biso Wilson estimate: 13.8 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 13
Reflection shellResolution: 1.4→1.48 Å / Redundancy: 5.2 % / Rmerge(I) obs: 0.51 / Mean I/σ(I) obs: 3.2 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHENIX(PHENIX.REFINE)refinement
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2J1X

2j1x


Resolution: 1.4→24.957 Å / SU ML: 0.18 / σ(F): 1.04 / Phase error: 19.74 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1922 -5 %
Rwork0.1763 --
obs0.1771 94496 99.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 40.276 Å2 / ksol: 0.367 e/Å3
Displacement parametersBiso mean: 19.5 Å2
Baniso -1Baniso -2Baniso -3
1-4.689 Å20 Å20 Å2
2---2.9568 Å20 Å2
3----1.7321 Å2
Refinement stepCycle: LAST / Resolution: 1.4→24.957 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3081 0 64 617 3762
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0063319
X-RAY DIFFRACTIONf_angle_d1.0594531
X-RAY DIFFRACTIONf_dihedral_angle_d13.541275
X-RAY DIFFRACTIONf_chiral_restr0.073493
X-RAY DIFFRACTIONf_plane_restr0.006596
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.4-1.41590.27992870.26245854X-RAY DIFFRACTION99
1.4159-1.43260.28122810.25095816X-RAY DIFFRACTION99
1.4326-1.450.26062990.24975894X-RAY DIFFRACTION99
1.45-1.46840.25323210.23275797X-RAY DIFFRACTION99
1.4684-1.48770.24193290.22665849X-RAY DIFFRACTION99
1.4877-1.50810.22963140.21725838X-RAY DIFFRACTION99
1.5081-1.52960.22383190.21035780X-RAY DIFFRACTION99
1.5296-1.55250.21923140.2025862X-RAY DIFFRACTION99
1.5525-1.57670.20293040.18675803X-RAY DIFFRACTION100
1.5767-1.60260.2083200.18825840X-RAY DIFFRACTION99
1.6026-1.63020.20443290.18175858X-RAY DIFFRACTION100
1.6302-1.65980.18243530.17545781X-RAY DIFFRACTION100
1.6598-1.69170.17942940.16775892X-RAY DIFFRACTION99
1.6917-1.72630.20963390.17535780X-RAY DIFFRACTION99
1.7263-1.76380.20342960.1735857X-RAY DIFFRACTION99
1.7638-1.80480.16683180.16635785X-RAY DIFFRACTION99
1.8048-1.84990.20673580.16765782X-RAY DIFFRACTION99
1.8499-1.89990.18733310.16715796X-RAY DIFFRACTION99
1.8999-1.95580.19673040.15975854X-RAY DIFFRACTION99
1.9558-2.01890.17292920.16655812X-RAY DIFFRACTION99
2.0189-2.0910.19043030.16215875X-RAY DIFFRACTION99
2.091-2.17470.18983340.16415752X-RAY DIFFRACTION99
2.1747-2.27360.17952970.1625766X-RAY DIFFRACTION98
2.2736-2.39340.18272910.16615748X-RAY DIFFRACTION97
2.3934-2.54320.16993040.16895806X-RAY DIFFRACTION99
2.5432-2.73940.17633230.1715778X-RAY DIFFRACTION98
2.7394-3.01460.18062870.16845761X-RAY DIFFRACTION98
3.0146-3.44990.18232740.16015674X-RAY DIFFRACTION96
3.4499-4.34270.15622970.15035736X-RAY DIFFRACTION97
4.3427-24.96050.17132470.175730X-RAY DIFFRACTION97

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