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- PDB-5g4n: Crystal structure of the p53 cancer mutant Y220C in complex with ... -

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Basic information

Entry
Database: PDB / ID: 5g4n
TitleCrystal structure of the p53 cancer mutant Y220C in complex with a difluorinated derivative of the small molecule stabilizer Phikan083
ComponentsCELLULAR TUMOR ANTIGEN P53
KeywordsTRANSCRIPTION / P53 / CANCER / TUMOR SUPPRESSION / DNA BINDING / CANCER THERAPY / SMALL-MOLECULE STABILIZERS / MOLECULAR CHAPERONE / FLUORINE-PROTEIN INTERACTIONS
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-O83 / Cellular tumor antigen p53
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.35 Å
AuthorsJoerger, A.C. / Bauer, M. / Jones, R.N. / Spencer, J.
CitationJournal: Acs Chem.Biol. / Year: 2016
Title: Harnessing Fluorine-Sulfur Contacts and Multipolar Interactions for the Design of P53 Mutant Y220C Rescue Drugs.
Authors: Bauer, M.R. / Jones, R.N. / Baud, M.G.J. / Wilcken, R. / Boeckler, F.M. / Fersht, A.R. / Joerger, A.C. / Spencer, J.
History
DepositionMay 13, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 22, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 28, 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)49,8337
Polymers49,0622
Non-polymers7725
Water7,728429
1
A: CELLULAR TUMOR ANTIGEN P53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,8713
Polymers24,5311
Non-polymers3402
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: CELLULAR TUMOR ANTIGEN P53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,9634
Polymers24,5311
Non-polymers4323
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)65.046, 71.139, 105.168
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 / P53 / ANTIGEN NY-CO-13 / PHOSPHOPROTEIN P53 / TUMOR SUPPRESSOR 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-O83 / 1-[9-(2,2-difluoroethyl)-9H-carbazol-3-yl]-N-methylmethanamine


Mass: 274.308 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H16F2N2
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 429 / 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: SATURATED SOLUTION OF 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: 0.9795
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.35→29.6 Å / Num. obs: 107270 / % possible obs: 99.7 % / Observed criterion σ(I): 2 / Redundancy: 4.9 % / Biso Wilson estimate: 14.02 Å2 / Rmerge(I) obs: 0.04 / Net I/σ(I): 16.2
Reflection shellResolution: 1.35→1.42 Å / Redundancy: 4.9 % / Rmerge(I) obs: 0.55 / Mean I/σ(I) obs: 3.5 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHENIX(DEV_2386: ???)refinement
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2J1X

2j1x


Resolution: 1.35→28.474 Å / SU ML: 0.1 / σ(F): 1.34 / Phase error: 16.02 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1675 5323 5 %
Rwork0.1465 --
obs0.1475 107149 99.59 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.35→28.474 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3082 0 48 429 3559
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0053302
X-RAY DIFFRACTIONf_angle_d0.84497
X-RAY DIFFRACTIONf_dihedral_angle_d19.4011264
X-RAY DIFFRACTIONf_chiral_restr0.083487
X-RAY DIFFRACTIONf_plane_restr0.006589
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.35-1.36530.22311610.19273366X-RAY DIFFRACTION100
1.3653-1.38140.20691940.18273339X-RAY DIFFRACTION100
1.3814-1.39830.2281730.17123407X-RAY DIFFRACTION100
1.3983-1.4160.19941800.16283336X-RAY DIFFRACTION100
1.416-1.43460.17461690.15713358X-RAY DIFFRACTION100
1.4346-1.45420.18351650.15243411X-RAY DIFFRACTION100
1.4542-1.4750.18541740.14253361X-RAY DIFFRACTION100
1.475-1.4970.16351730.13913363X-RAY DIFFRACTION100
1.497-1.52040.1651510.12833401X-RAY DIFFRACTION100
1.5204-1.54530.16861680.13193384X-RAY DIFFRACTION100
1.5453-1.5720.16881670.12623384X-RAY DIFFRACTION100
1.572-1.60060.1711890.12493340X-RAY DIFFRACTION100
1.6006-1.63140.15471930.12033387X-RAY DIFFRACTION100
1.6314-1.66460.15111840.11823390X-RAY DIFFRACTION100
1.6646-1.70080.14481870.11533381X-RAY DIFFRACTION100
1.7008-1.74040.15341840.1223347X-RAY DIFFRACTION100
1.7404-1.78390.14381880.1233397X-RAY DIFFRACTION100
1.7839-1.83210.15232000.12353340X-RAY DIFFRACTION100
1.8321-1.8860.15462000.13473368X-RAY DIFFRACTION100
1.886-1.94690.16931740.12973399X-RAY DIFFRACTION100
1.9469-2.01650.1511690.13773421X-RAY DIFFRACTION100
2.0165-2.09720.16411800.13433435X-RAY DIFFRACTION100
2.0972-2.19260.1691960.13983352X-RAY DIFFRACTION99
2.1926-2.30810.1691600.14573398X-RAY DIFFRACTION99
2.3081-2.45270.16231770.15053400X-RAY DIFFRACTION99
2.4527-2.64190.16761850.1573402X-RAY DIFFRACTION99
2.6419-2.90760.17931730.1643405X-RAY DIFFRACTION99
2.9076-3.32770.18011640.1573449X-RAY DIFFRACTION98
3.3277-4.19050.1711850.14953469X-RAY DIFFRACTION99
4.1905-28.48010.16061600.1633636X-RAY DIFFRACTION99

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