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- PDB-5lap: p53 cancer mutant Y220C with Cys182 alkylation -

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Basic information

Entry
Database: PDB / ID: 5lap
Titlep53 cancer mutant Y220C with Cys182 alkylation
ComponentsCellular tumor antigen p53
KeywordsDNA BINDING PROTEIN / p53 / tumor suppressor / cancer mutation / protein stabilization / alkylating agents / 2-sulfonylpyrimidines / cancer therapy
Function / homology
Function and homology information


negative regulation of helicase activity / signal transduction by p53 class mediator / Loss of function of TP53 in cancer due to loss of tetramerization ability / Regulation of TP53 Expression / regulation of cell cycle G2/M phase transition / negative regulation of G1 to G0 transition / Transcriptional activation of cell cycle inhibitor p21 / negative regulation of pentose-phosphate shunt / Activation of NOXA and translocation to mitochondria / ATP-dependent DNA/DNA annealing activity ...negative regulation of helicase activity / signal transduction by p53 class mediator / Loss of function of TP53 in cancer due to loss of tetramerization ability / Regulation of TP53 Expression / regulation of cell cycle G2/M phase transition / negative regulation of G1 to G0 transition / Transcriptional activation of cell cycle inhibitor p21 / negative regulation of pentose-phosphate shunt / Activation of NOXA and translocation to mitochondria / ATP-dependent DNA/DNA annealing activity / oligodendrocyte apoptotic process / positive regulation of thymocyte apoptotic process / oxidative stress-induced premature senescence / bone marrow development / cellular response to actinomycin D / circadian behavior / positive regulation of programmed necrotic cell death / RUNX3 regulates CDKN1A transcription / 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 / Regulation of TP53 Activity through Association with Co-factors / Urea cycle / ER overload response / hematopoietic stem cell differentiation / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / TP53 Regulates Transcription of Caspase Activators and Caspases / intrinsic apoptotic signaling pathway by p53 class mediator / entrainment of circadian clock by photoperiod / Zygotic genome activation (ZGA) / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / PI5P Regulates TP53 Acetylation / positive regulation of release of cytochrome c from mitochondria / hematopoietic progenitor cell differentiation / Association of TriC/CCT with target proteins during biosynthesis / negative regulation of telomere maintenance via telomerase / 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 in response to DNA damage by p53 class mediator / Transcriptional Regulation by VENTX / TFIID-class transcription factor complex binding / replicative senescence / viral process / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / Pyroptosis / determination of adult lifespan / positive regulation of RNA polymerase II transcription preinitiation complex assembly / general transcription initiation factor binding / negative regulation of fibroblast proliferation / positive regulation of execution phase of apoptosis / type II interferon-mediated signaling pathway / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / cellular response to glucose starvation / core promoter sequence-specific DNA binding / cis-regulatory region sequence-specific DNA binding / Regulation of TP53 Activity through Acetylation / intrinsic apoptotic signaling pathway / mitotic G1 DNA damage checkpoint signaling / positive regulation of intrinsic apoptotic signaling pathway / response to gamma radiation / 14-3-3 protein binding / MDM2/MDM4 family protein binding / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / DNA damage response, signal transduction by p53 class mediator / protein phosphatase 2A binding / transcription initiation-coupled chromatin remodeling / molecular function activator activity / Regulation of PTEN gene transcription / tumor necrosis factor-mediated signaling pathway / cellular response to ionizing radiation / cellular response to xenobiotic stimulus / TP53 Regulates Metabolic Genes / TP53 Regulates Transcription of DNA Repair Genes / cellular response to gamma radiation / Regulation of NF-kappa B signaling / mRNA 3'-UTR binding / protein tetramerization / promoter-specific chromatin binding / Stabilization of p53 / molecular condensate scaffold activity / negative regulation of cell growth / nucleotide-excision repair / G2/M Checkpoints / receptor tyrosine kinase binding / Autodegradation of the E3 ubiquitin ligase COP1 / cellular senescence / PML body / PKR-mediated signaling / positive regulation of miRNA transcription / Oncogene Induced Senescence / DNA-binding transcription repressor activity, RNA polymerase II-specific / Regulation of TP53 Activity through Methylation / G2/M DNA damage checkpoint / DNA Damage/Telomere Stress Induced Senescence / Pre-NOTCH Transcription and Translation / transcription coactivator binding / positive regulation of reactive oxygen species metabolic process / intracellular protein localization / histone deacetylase binding
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 ...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
5-chloranylpyrimidine-4-carboxylic acid / Cellular tumor antigen p53
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.42 Å
AuthorsJoerger, A.C. / Bauer, M.R. / Fersht, A.R.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2016
Title: 2-Sulfonylpyrimidines: Mild alkylating agents with anticancer activity toward p53-compromised cells.
Authors: Bauer, M.R. / Joerger, A.C. / Fersht, A.R.
History
DepositionJun 14, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 10, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 7, 2016Group: Database references
Revision 1.2Sep 14, 2016Group: Database references
Revision 1.3Jan 10, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / struct_conn_type
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _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_asym_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_type.id
Revision 1.4Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)49,5106
Polymers49,0622
Non-polymers4484
Water9,746541
1
A: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,7553
Polymers24,5311
Non-polymers2242
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,7553
Polymers24,5311
Non-polymers2242
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)65.108, 71.085, 105.252
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 / Mutation: M133L, V203A, Y220C, N239Y, N268D
Source method: isolated from a genetically manipulated source
Details: DNA-binding domain / Source: (gene. exp.) Homo sapiens (human) / Gene: TP53, P53 / 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-6SM / 5-chloranylpyrimidine-4-carboxylic acid


Mass: 158.543 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C5H3ClN2O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 541 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.5 Å3/Da / Density % sol: 51 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 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 ...Details: 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 Phikan11000 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: 0.976 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Mar 9, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 1.42→58.91 Å / Num. obs: 92560 / % possible obs: 99.8 % / Redundancy: 5.5 % / Rmerge(I) obs: 0.064 / Net I/σ(I): 17.4
Reflection shellResolution: 1.42→1.5 Å / Redundancy: 5.3 % / Rmerge(I) obs: 0.57 / Mean I/σ(I) obs: 3.9 / % possible all: 99.5

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Processing

SoftwareName: REFMAC / Version: 5.8.0151 / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2J1X

2j1x


Resolution: 1.42→58.91 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.956 / SU B: 0.941 / SU ML: 0.037 / Cross valid method: THROUGHOUT / ESU R: 0.058 / ESU R Free: 0.057 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.19321 4694 5.1 %RANDOM
Rwork0.17783 ---
obs0.17862 87789 99.74 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 15.23 Å2
Baniso -1Baniso -2Baniso -3
1-1.08 Å2-0 Å20 Å2
2---0.86 Å2-0 Å2
3----0.22 Å2
Refinement stepCycle: LAST / Resolution: 1.42→58.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3066 0 22 541 3629
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0193238
X-RAY DIFFRACTIONr_bond_other_d0.0020.022998
X-RAY DIFFRACTIONr_angle_refined_deg1.3061.974413
X-RAY DIFFRACTIONr_angle_other_deg0.95436926
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0975405
X-RAY DIFFRACTIONr_dihedral_angle_2_deg28.81522.252151
X-RAY DIFFRACTIONr_dihedral_angle_3_deg10.5415539
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.7791537
X-RAY DIFFRACTIONr_chiral_restr0.0770.2483
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0213680
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02763
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.8841.3361581
X-RAY DIFFRACTIONr_mcbond_other0.8821.3331580
X-RAY DIFFRACTIONr_mcangle_it1.5351.9981978
X-RAY DIFFRACTIONr_mcangle_other1.5352.0011979
X-RAY DIFFRACTIONr_scbond_it1.191.4881657
X-RAY DIFFRACTIONr_scbond_other1.1871.4871656
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.9372.1692429
X-RAY DIFFRACTIONr_long_range_B_refined6.1519.6334015
X-RAY DIFFRACTIONr_long_range_B_other6.14919.6334016
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.42→1.457 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3 344 -
Rwork0.289 6376 -
obs--98.98 %

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