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- PDB-5ab9: Structure of the p53 cancer mutant Y220C with bound small molecul... -

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Basic information

Entry
Database: PDB / ID: 5ab9
TitleStructure of the p53 cancer mutant Y220C with bound small molecule 7- ethyl-3-(piperidin-4-yl)-1H-indole
ComponentsCELLULAR TUMOR ANTIGEN P53
KeywordsTRANSCRIPTION / CANCER / TUMOR SUPPRESSION / DNA BINDING / CANCER THERAPY / SMALL-MOLECULE STABILIZERS / MOLECULAR CHAPERONE
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 / ATP-dependent DNA/DNA annealing activity ...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 / ATP-dependent DNA/DNA annealing activity / Activation of NOXA and translocation to mitochondria / regulation of cell cycle G2/M phase transition / regulation of fibroblast apoptotic process / 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 / mRNA transcription / bone marrow development / positive regulation of programmed necrotic cell death / circadian behavior / T cell proliferation involved in immune response / regulation of mitochondrial membrane permeability involved in apoptotic process / germ cell nucleus / RUNX3 regulates CDKN1A transcription / glucose catabolic process to lactate via pyruvate / 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 / regulation of DNA damage response, signal transduction by p53 class mediator / histone deacetylase regulator activity / negative regulation of glial cell proliferation / Regulation of TP53 Activity through Association with Co-factors / negative regulation of neuroblast proliferation / mitochondrial DNA repair / T cell lineage commitment / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / ER overload response / thymocyte apoptotic process / B cell lineage commitment / TP53 Regulates Transcription of Caspase Activators and Caspases / cardiac septum morphogenesis / negative regulation of mitophagy / negative regulation of DNA replication / entrainment of circadian clock by photoperiod / negative regulation of telomere maintenance via telomerase / Zygotic genome activation (ZGA) / positive regulation of release of cytochrome c from mitochondria / PI5P Regulates TP53 Acetylation / Association of TriC/CCT with target proteins during biosynthesis / necroptotic process / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / TFIID-class transcription factor complex binding / 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 by p53 class mediator / negative regulation of reactive oxygen species metabolic process / rRNA transcription / Transcriptional Regulation by VENTX / cellular response to UV-C / replicative senescence / general transcription initiation factor binding / cellular response to actinomycin D / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / positive regulation of RNA polymerase II transcription preinitiation complex assembly / positive regulation of execution phase of apoptosis / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / neuroblast proliferation / Pyroptosis / hematopoietic stem cell differentiation / viral process / response to X-ray / embryonic organ development / chromosome organization / type II interferon-mediated signaling pathway / somitogenesis / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / hematopoietic progenitor cell differentiation / glial cell proliferation / negative regulation of fibroblast proliferation / core promoter sequence-specific DNA binding / positive regulation of cardiac muscle cell apoptotic process / negative regulation of stem cell proliferation / cellular response to glucose starvation / mitophagy / cis-regulatory region sequence-specific DNA binding / positive regulation of intrinsic apoptotic signaling pathway / Regulation of TP53 Activity through Acetylation / gastrulation / response to salt stress / 14-3-3 protein binding / mitotic G1 DNA damage checkpoint signaling / negative regulation of proteolysis / MDM2/MDM4 family protein binding / cardiac muscle cell apoptotic process / transcription repressor complex / intrinsic apoptotic signaling pathway
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
7-ethyl-3-(piperidin-4-yl)-1H-indole / DI(HYDROXYETHYL)ETHER / Cellular tumor antigen p53
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.36 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
DepositionAug 4, 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.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)50,2129
Polymers49,0622
Non-polymers1,1507
Water7,656425
1
A: CELLULAR TUMOR ANTIGEN P53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,1595
Polymers24,5311
Non-polymers6284
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: CELLULAR TUMOR ANTIGEN P53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,0534
Polymers24,5311
Non-polymers5223
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)64.994, 71.059, 105.028
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 / 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-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#4: Chemical
ChemComp-92O / 7-ethyl-3-(piperidin-4-yl)-1H-indole


Mass: 228.333 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C15H20N2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 425 / 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: 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: 40 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: 1.36→29.6 Å / Num. obs: 103976 / % possible obs: 99.2 % / Observed criterion σ(I): 2 / Redundancy: 5.4 % / Biso Wilson estimate: 13.73 Å2 / Rmerge(I) obs: 0.05 / Net I/σ(I): 15.2
Reflection shellResolution: 1.36→1.43 Å / Redundancy: 5.4 % / Rmerge(I) obs: 0.59 / Mean I/σ(I) obs: 3.7 / % possible all: 98.6

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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: 1.36→29.427 Å / SU ML: 0.1 / σ(F): 1.34 / Phase error: 15.41 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1655 5243 5.1 %
Rwork0.143 --
obs0.1441 103859 99 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 21 Å2
Refinement stepCycle: LAST / Resolution: 1.36→29.427 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3075 0 72 425 3572
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0063362
X-RAY DIFFRACTIONf_angle_d1.0474598
X-RAY DIFFRACTIONf_dihedral_angle_d11.8321320
X-RAY DIFFRACTIONf_chiral_restr0.044496
X-RAY DIFFRACTIONf_plane_restr0.007603
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.36-1.37550.23411710.20463210X-RAY DIFFRACTION98
1.3755-1.39170.23481950.19093201X-RAY DIFFRACTION98
1.3917-1.40860.21231910.17113212X-RAY DIFFRACTION99
1.4086-1.42650.17991810.16013219X-RAY DIFFRACTION98
1.4265-1.44520.19551600.15153227X-RAY DIFFRACTION98
1.4452-1.4650.18831550.14583253X-RAY DIFFRACTION99
1.465-1.4860.19131660.14213270X-RAY DIFFRACTION98
1.486-1.50810.16971740.13523236X-RAY DIFFRACTION99
1.5081-1.53170.14741730.13093283X-RAY DIFFRACTION99
1.5317-1.55680.17251830.12983206X-RAY DIFFRACTION99
1.5568-1.58360.17271780.1213315X-RAY DIFFRACTION99
1.5836-1.61240.15441570.11783237X-RAY DIFFRACTION99
1.6124-1.64350.14731810.11453252X-RAY DIFFRACTION99
1.6435-1.6770.13431680.1123289X-RAY DIFFRACTION99
1.677-1.71350.15661910.1163272X-RAY DIFFRACTION99
1.7135-1.75330.14121710.11653241X-RAY DIFFRACTION99
1.7533-1.79720.14751810.11763303X-RAY DIFFRACTION99
1.7972-1.84570.17212040.12133262X-RAY DIFFRACTION99
1.8457-1.90.16381780.13333281X-RAY DIFFRACTION99
1.9-1.96140.15411820.12553307X-RAY DIFFRACTION100
1.9614-2.03140.14721510.13413320X-RAY DIFFRACTION99
2.0314-2.11280.16031830.13453294X-RAY DIFFRACTION100
2.1128-2.20890.18061850.13553274X-RAY DIFFRACTION99
2.2089-2.32530.15611670.14083346X-RAY DIFFRACTION99
2.3253-2.47090.17591680.14963333X-RAY DIFFRACTION99
2.4709-2.66160.16041710.15853315X-RAY DIFFRACTION99
2.6616-2.92920.18851760.16513349X-RAY DIFFRACTION99
2.9292-3.35250.18751620.1563351X-RAY DIFFRACTION99
3.3525-4.22190.15161800.14193400X-RAY DIFFRACTION99
4.2219-29.4340.15391600.15473558X-RAY DIFFRACTION99

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