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- PDB-4agn: Structure of the p53 core domain mutant Y220C bound to the stabil... -

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Basic information

Entry
Database: PDB / ID: 4agn
TitleStructure of the p53 core domain mutant Y220C bound to the stabilizing small molecule PhiKan5116
ComponentsCELLULAR TUMOR ANTIGEN P53
KeywordsCELL CYCLE / TRANSCRIPTION / APOPTOSIS / CANCER MUTATION / SURFACE CREVICE / SMALL-MOLECULE DRUG / PROTEIN STABILIZATION / HALOGEN BONDING / ACETYLENE LINKER / ZINC BINDING
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 / circadian behavior / bone marrow development / histone deacetylase regulator activity / germ cell nucleus / 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 / negative regulation of glial cell proliferation / negative regulation of neuroblast proliferation / Regulation of TP53 Activity through Association with Co-factors / mitochondrial DNA repair / T cell lineage commitment / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / ER overload response / negative regulation of DNA replication / 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 / cardiac septum morphogenesis / entrainment of circadian clock by photoperiod / PI5P Regulates TP53 Acetylation / Association of TriC/CCT with target proteins during biosynthesis / positive regulation of release of cytochrome c from mitochondria / 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 / Transcriptional Regulation by VENTX / DNA damage response, signal transduction by p53 class mediator / replicative senescence / response to X-ray / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / mitophagy / cellular response to UV-C / positive regulation of RNA polymerase II transcription preinitiation complex assembly / hematopoietic stem cell differentiation / neuroblast proliferation / negative regulation of reactive oxygen species metabolic process / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / chromosome organization / T cell proliferation involved in immune response / Pyroptosis / embryonic organ development / 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 / type II interferon-mediated signaling pathway / somitogenesis / cellular response to actinomycin D / core promoter sequence-specific DNA binding / cellular response to glucose starvation / negative regulation of stem cell proliferation / positive regulation of intrinsic apoptotic signaling pathway / negative regulation of fibroblast proliferation / gastrulation / MDM2/MDM4 family protein binding / response to salt stress / cardiac muscle cell apoptotic process / mitotic G1 DNA damage checkpoint signaling / tumor necrosis factor-mediated signaling pathway / 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-NXG / Cellular tumor antigen p53
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsJoerger, A.C. / Wilcken, R. / Boeckler, F.M. / Fersht, A.R.
Citation
Journal: J.Am.Chem.Soc. / Year: 2012
Title: Halogen-Enriched Fragment Libraries as Leads for Drug Rescue of Mutant P53.
Authors: Wilcken, R. / Liu, X. / Zimmermann, M.O. / Rutherford, T.J. / Fersht, A.R. / Joerger, A.C. / Boeckler, F.M.
#1: Journal: Proc.Natl.Acad.Sci.USA / Year: 2006
Title: Structural Basis for Understanding Oncogenic P53 Mutations and Designing Rescue Drugs.
Authors: Joerger, A.C. / Ang, H.C. / Fersht, A.R.
History
DepositionJan 30, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 21, 2012Provider: repository / Type: Initial release
Revision 1.1May 2, 2012Group: Other
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 1.4Dec 20, 2023Group: 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

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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)50,0776
Polymers49,0622
Non-polymers1,0154
Water10,971609
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A: CELLULAR TUMOR ANTIGEN P53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,0393
Polymers24,5311
Non-polymers5082
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: CELLULAR TUMOR ANTIGEN P53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,0393
Polymers24,5311
Non-polymers5082
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)65.040, 71.260, 104.880
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, 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-NXG / 2-{[4-(DIETHYLAMINO)PIPERIDIN-1-YL]METHYL}-4-(3-HYDROXYPROP-1-YN-1-YL)-6-IODOPHENOL


Mass: 442.334 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H27IN2O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 609 / Source method: isolated from a natural source / Formula: H2O
Compound detailsENGINEERED RESIDUE IN CHAIN A, MET 133 TO LEU ENGINEERED RESIDUE IN CHAIN A, VAL 203 TO ALA ...ENGINEERED RESIDUE IN CHAIN A, MET 133 TO LEU ENGINEERED RESIDUE IN CHAIN A, VAL 203 TO ALA ENGINEERED RESIDUE IN CHAIN A, TYR 220 TO CYS ENGINEERED RESIDUE IN CHAIN A, ASN 239 TO TYR ENGINEERED RESIDUE IN CHAIN A, ASN 268 TO ASP ENGINEERED RESIDUE IN CHAIN B, MET 133 TO LEU ENGINEERED RESIDUE IN CHAIN B, VAL 203 TO ALA ENGINEERED RESIDUE IN CHAIN B, TYR 220 TO CYS ENGINEERED RESIDUE IN CHAIN B, ASN 239 TO TYR ENGINEERED RESIDUE IN CHAIN B, ASN 268 TO ASP

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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: 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: I02 / Wavelength: 0.9791
DetectorType: ADSC CCD / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 1.6→35.4 Å / Num. obs: 64327 / % possible obs: 99 % / Observed criterion σ(I): 2 / Redundancy: 5.4 % / Biso Wilson estimate: 11.89 Å2 / Rmerge(I) obs: 0.08 / Net I/σ(I): 12.9
Reflection shellResolution: 1.6→1.69 Å / Redundancy: 5.3 % / Rmerge(I) obs: 0.31 / Mean I/σ(I) obs: 4.4 / % possible all: 97

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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: 1.6→24.607 Å / SU ML: 0.18 / σ(F): 0.43 / Phase error: 17.92 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1942 3230 5 %
Rwork0.1742 --
obs0.1752 64140 98.68 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 40.379 Å2 / ksol: 0.375 e/Å3
Displacement parametersBiso mean: 16.8 Å2
Baniso -1Baniso -2Baniso -3
1-3.5191 Å20 Å20 Å2
2---0.9548 Å20 Å2
3----2.5643 Å2
Refinement stepCycle: LAST / Resolution: 1.6→24.607 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3090 0 50 609 3749
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0063284
X-RAY DIFFRACTIONf_angle_d1.0744464
X-RAY DIFFRACTIONf_dihedral_angle_d13.7621271
X-RAY DIFFRACTIONf_chiral_restr0.077492
X-RAY DIFFRACTIONf_plane_restr0.006580
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6-1.62390.24611280.21362579X-RAY DIFFRACTION96
1.6239-1.64930.25381530.20082529X-RAY DIFFRACTION97
1.6493-1.67630.22051470.19542556X-RAY DIFFRACTION97
1.6763-1.70520.21221400.19072563X-RAY DIFFRACTION97
1.7052-1.73620.23111460.18452608X-RAY DIFFRACTION98
1.7362-1.76960.20841430.17632571X-RAY DIFFRACTION98
1.7696-1.80570.20071420.17532629X-RAY DIFFRACTION98
1.8057-1.84490.18691680.16572592X-RAY DIFFRACTION99
1.8449-1.88780.17481440.16912613X-RAY DIFFRACTION99
1.8878-1.9350.22281310.16532624X-RAY DIFFRACTION99
1.935-1.98730.20311320.17552662X-RAY DIFFRACTION99
1.9873-2.04580.21391350.17592646X-RAY DIFFRACTION99
2.0458-2.11180.19271560.1722650X-RAY DIFFRACTION100
2.1118-2.18720.19541490.16582651X-RAY DIFFRACTION99
2.1872-2.27470.18891260.15822662X-RAY DIFFRACTION100
2.2747-2.37820.20751320.16892687X-RAY DIFFRACTION99
2.3782-2.50340.18791410.17062673X-RAY DIFFRACTION100
2.5034-2.66010.19051400.17342680X-RAY DIFFRACTION100
2.6601-2.86520.21911500.16952682X-RAY DIFFRACTION100
2.8652-3.1530.17161330.16982705X-RAY DIFFRACTION99
3.153-3.6080.17161370.15442737X-RAY DIFFRACTION99
3.608-4.54110.14341280.15012734X-RAY DIFFRACTION98
4.5411-24.610.16621290.18512877X-RAY DIFFRACTION99

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