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- PDB-5aok: Structure of the p53 cancer mutant Y220C with bound small molecul... -

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Basic information

Entry
Database: PDB / ID: 5aok
TitleStructure of the p53 cancer mutant Y220C with bound small molecule PhiKan7099
ComponentsCELLULAR TUMOR ANTIGEN P53
KeywordsCELL CYCLE / P53 / CANCER / TUMOR SUPPRESSION / 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-GOH / DI(HYDROXYETHYL)ETHER / Cellular tumor antigen p53
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.35 Å
AuthorsJoerger, A.C.
CitationJournal: Structure / Year: 2015
Title: Exploiting Transient Protein States for the Design of Small-Molecule Stabilizers of Mutant P53.
Authors: Joerger, A.C. / Bauer, M.R. / Wilcken, R. / Baud, M.G.J. / Harbrecht, H. / Exner, T.E. / Boeckler, F.M. / Spencer, J. / Fersht, A.R.
History
DepositionSep 10, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 16, 2015Provider: repository / Type: Initial release
Revision 1.1May 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 1.2May 15, 2019Group: Data collection / Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.method
Revision 1.3Jan 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.pdbx_ptnr1_label_alt_id / _struct_conn.pdbx_ptnr2_label_alt_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_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)49,9679
Polymers49,0622
Non-polymers9067
Water10,196566
1
A: CELLULAR TUMOR ANTIGEN P53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,9314
Polymers24,5311
Non-polymers4003
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: CELLULAR TUMOR ANTIGEN P53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,0375
Polymers24,5311
Non-polymers5064
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)65.013, 70.989, 105.177
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

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

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Non-polymers , 5 types, 573 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-GOH / 5-[2-cyclopropyl-5-(1H-pyrrol-1-yl)-1,3-oxazol-4-yl]-1H-1,2,3,4-tetrazole


Mass: 242.237 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C11H10N6O
#5: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 566 / Source method: isolated from a natural source / Formula: H2O

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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 % / Description: NONE
Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop
Details: 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) ...Details: 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: 38 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: I04 / Wavelength: 1.0163
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0163 Å / Relative weight: 1
ReflectionResolution: 1.35→29.5 Å / Num. obs: 103354 / % possible obs: 96.5 % / Observed criterion σ(I): 2 / Redundancy: 6.1 % / Biso Wilson estimate: 10.49 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 15.5
Reflection shellResolution: 1.35→1.42 Å / Redundancy: 5.9 % / Rmerge(I) obs: 0.46 / Mean I/σ(I) obs: 3.7 / % possible all: 94.2

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Processing

SoftwareName: PHENIX / Version: (PHENIX.REFINE) / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2J1X

2j1x


Resolution: 1.35→29.42 Å / SU ML: 0.11 / σ(F): 1.35 / Phase error: 15.6 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.169 5183 5 %
Rwork0.1446 --
obs0.1458 103279 96.23 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 16.5 Å2
Refinement stepCycle: LAST / Resolution: 1.35→29.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3081 0 57 566 3704
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0063323
X-RAY DIFFRACTIONf_angle_d1.0764532
X-RAY DIFFRACTIONf_dihedral_angle_d13.781300
X-RAY DIFFRACTIONf_chiral_restr0.045490
X-RAY DIFFRACTIONf_plane_restr0.007599
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.35-1.36530.26941720.2093143X-RAY DIFFRACTION93
1.3653-1.38140.23521960.23108X-RAY DIFFRACTION94
1.3814-1.39830.20091560.18053197X-RAY DIFFRACTION95
1.3983-1.4160.19661560.16923178X-RAY DIFFRACTION94
1.416-1.43460.22181640.16273168X-RAY DIFFRACTION95
1.4346-1.45420.16791600.14933200X-RAY DIFFRACTION94
1.4542-1.4750.19811470.13743192X-RAY DIFFRACTION95
1.475-1.4970.18441630.13113221X-RAY DIFFRACTION95
1.497-1.52040.17041760.13423181X-RAY DIFFRACTION95
1.5204-1.54530.16651830.13183203X-RAY DIFFRACTION95
1.5453-1.5720.16671540.12873217X-RAY DIFFRACTION95
1.572-1.60060.16241880.12673194X-RAY DIFFRACTION96
1.6006-1.63140.161830.12243248X-RAY DIFFRACTION96
1.6314-1.66470.1541760.12063242X-RAY DIFFRACTION96
1.6647-1.70080.15841780.11873234X-RAY DIFFRACTION96
1.7008-1.74040.14671770.1183244X-RAY DIFFRACTION96
1.7404-1.78390.14791830.1143254X-RAY DIFFRACTION97
1.7839-1.83210.14641960.12073224X-RAY DIFFRACTION97
1.8321-1.88610.16141950.13193271X-RAY DIFFRACTION97
1.8861-1.94690.18761700.12933301X-RAY DIFFRACTION97
1.9469-2.01650.15181630.13363309X-RAY DIFFRACTION97
2.0165-2.09720.15141760.14023348X-RAY DIFFRACTION98
2.0972-2.19260.1771910.14363306X-RAY DIFFRACTION98
2.1926-2.30820.17511620.14523342X-RAY DIFFRACTION98
2.3082-2.45270.16951680.14843353X-RAY DIFFRACTION98
2.4527-2.6420.16011750.15273391X-RAY DIFFRACTION98
2.642-2.90770.1751760.15663383X-RAY DIFFRACTION99
2.9077-3.32790.18041640.15543413X-RAY DIFFRACTION98
3.3279-4.19090.17271780.14543444X-RAY DIFFRACTION98
4.1909-29.42730.14691570.16373587X-RAY DIFFRACTION97

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