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- PDB-6gge: p53 cancer mutant Y220C in complex with small-molecule stabilizer... -

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Basic information

Entry
Database: PDB / ID: 6gge
Titlep53 cancer mutant Y220C in complex with small-molecule stabilizer PK9327
ComponentsCellular tumor antigen p53P53
KeywordsDNA BINDING PROTEIN / p53 / transcription factor / tumor supressor / cancer therapy / oncogenic mutant / protein misfolding / small-molecule stabilizer / 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 ...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 / glucose catabolic process to lactate via pyruvate / regulation of tissue remodeling / 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 / T cell proliferation involved in immune response / regulation of mitochondrial membrane permeability involved in apoptotic process / RUNX3 regulates CDKN1A transcription / germ cell nucleus / 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 / negative regulation of neuroblast proliferation / DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / negative regulation of glial cell proliferation / Regulation of TP53 Activity through Association with Co-factors / positive regulation of execution phase of apoptosis / mitochondrial DNA repair / T cell lineage commitment / negative regulation of DNA replication / ER overload response / negative regulation of telomerase activity / 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 / entrainment of circadian clock by photoperiod / cardiac septum morphogenesis / PI5P Regulates TP53 Acetylation / Association of TriC/CCT with target proteins during biosynthesis / Zygotic genome activation (ZGA) / necroptotic process / positive regulation of release of cytochrome c from mitochondria / rRNA transcription / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / TFIID-class transcription factor complex binding / mitophagy / SUMOylation of transcription factors / intrinsic apoptotic signaling pathway by p53 class mediator / general transcription initiation factor binding / neuroblast proliferation / cellular response to actinomycin D / Transcriptional Regulation by VENTX / response to X-ray / DNA damage response, signal transduction by p53 class mediator / replicative senescence / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / chromosome organization / gastrulation / cellular response to UV-C / response to inorganic substance / hematopoietic stem cell differentiation / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / negative regulation of reactive oxygen species metabolic process / positive regulation of RNA polymerase II transcription preinitiation complex assembly / MDM2/MDM4 family protein binding / glial cell proliferation / embryonic organ development / cellular response to glucose starvation / Pyroptosis / cis-regulatory region sequence-specific DNA binding / hematopoietic progenitor cell differentiation / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / somitogenesis / type II interferon-mediated signaling pathway / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / positive regulation of intrinsic apoptotic signaling pathway / negative regulation of fibroblast proliferation / negative regulation of stem cell proliferation / core promoter sequence-specific DNA binding / cardiac muscle cell apoptotic process / response to salt stress / transcription initiation-coupled chromatin remodeling
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-EYE / Cellular tumor antigen p53
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.25000506704 Å
AuthorsJoerger, A.C. / Bauer, M.R.
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research FoundationJO 1473/1-1 Germany
Citation
Journal: Future Med Chem / Year: 2019
Title: A structure-guided molecular chaperone approach for restoring the transcriptional activity of the p53 cancer mutant Y220C.
Authors: Bauer, M.R. / Jones, R.N. / Tareque, R.K. / Springett, B. / Dingler, F.A. / Verduci, L. / Patel, K.J. / Fersht, A.R. / Joerger, A.C. / Spencer, J.
#1: Journal: Proc. Natl. Acad. Sci. U.S.A. / 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
DepositionMay 3, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 22, 2019Provider: repository / Type: Initial release
Revision 1.1Oct 30, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jan 17, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)49,8636
Polymers49,0622
Non-polymers8024
Water8,683482
1
A: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,9323
Polymers24,5311
Non-polymers4012
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,9323
Polymers24,5311
Non-polymers4012
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)65.075, 71.221, 105.268
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab

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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 / Mutation: M133L, V203A, Y220S,N239Y, N268D
Source method: isolated from a genetically manipulated source
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-EYE / [9-ethyl-7-(5-methylthiophen-2-yl)carbazol-3-yl]methyl-methyl-azanium


Mass: 335.486 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H23N2S
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 482 / 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 %
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: 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: I03 / Wavelength: 0.98 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Aug 8, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.25→29.6 Å / Num. obs: 129162 / % possible obs: 95.5 % / Redundancy: 5.3 % / Biso Wilson estimate: 13.1257049977 Å2 / Rmerge(I) obs: 0.054 / Net I/σ(I): 13.7
Reflection shellResolution: 1.25→1.32 Å / Redundancy: 5.4 % / Rmerge(I) obs: 0.58 / Mean I/σ(I) obs: 2.8 / % possible all: 93

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Processing

Software
NameVersionClassification
PHENIX1.10.1_2155refinement
XDSdata reduction
SCALAdata scaling
PHENIXphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 2J1X

2j1x


Resolution: 1.25000506704→29.4942478596 Å / SU ML: 0.101862459892 / Cross valid method: THROUGHOUT / σ(F): 1.32651126839 / Phase error: 16.5876228601
RfactorNum. reflection% reflection
Rfree0.170800413489 6544 5.07109922895 %
Rwork0.14989112458 --
obs0.150925464968 129045 95.2516275705 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 19.8700348951 Å2
Refinement stepCycle: LAST / Resolution: 1.25000506704→29.4942478596 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3026 0 50 482 3558
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.004804957521453237
X-RAY DIFFRACTIONf_angle_d0.8110905639234421
X-RAY DIFFRACTIONf_chiral_restr0.0843845448412488
X-RAY DIFFRACTIONf_plane_restr0.00675212247725577
X-RAY DIFFRACTIONf_dihedral_angle_d16.96067261961203
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.25-1.26420.2405693356642200.2109197742143900X-RAY DIFFRACTION92.5842696629
1.2642-1.27910.2246975217922470.2040276525233885X-RAY DIFFRACTION92.8956834532
1.2791-1.29470.2328827966891880.1960643035263947X-RAY DIFFRACTION92.381590706
1.2947-1.31110.2181217591592130.1934517573043963X-RAY DIFFRACTION93.4437234281
1.3111-1.32830.2045808057742090.1791328683533953X-RAY DIFFRACTION92.8396163284
1.3283-1.34650.1937124338852250.1745789284443860X-RAY DIFFRACTION91.4893617021
1.3465-1.36580.2083520420222250.1710380621563958X-RAY DIFFRACTION93.6003580219
1.3658-1.38610.2000525316092140.1701600306454021X-RAY DIFFRACTION93.9024390244
1.3861-1.40780.1773404223442060.1587144453273973X-RAY DIFFRACTION94.2915162455
1.4078-1.43090.1632599604531920.1523532255354036X-RAY DIFFRACTION94.1648106904
1.4309-1.45560.1669352482852190.1509930777694029X-RAY DIFFRACTION94.3790268829
1.4556-1.4820.1719568692392220.1412331248494017X-RAY DIFFRACTION94.6839401385
1.482-1.51050.1555671445742220.134544800814037X-RAY DIFFRACTION95.088189328
1.5105-1.54140.1625722653032380.1312330844594004X-RAY DIFFRACTION94.9205638845
1.5414-1.57490.1667821977042180.1316240833134049X-RAY DIFFRACTION95.2455357143
1.5749-1.61150.1439320194051860.1309339085614126X-RAY DIFFRACTION95.2086553323
1.6115-1.65180.1384597842592060.1218843938044007X-RAY DIFFRACTION93.9144003567
1.6518-1.69650.1464848820032300.1223281636724079X-RAY DIFFRACTION95.840747331
1.6965-1.74640.1515483751362210.1267456098474122X-RAY DIFFRACTION96.3398402839
1.7464-1.80270.1490129093192350.1274880196064101X-RAY DIFFRACTION96.4627363737
1.8027-1.86710.1593963698922530.1350906527694129X-RAY DIFFRACTION96.6902030009
1.8671-1.94190.1739951723162190.1374189396684140X-RAY DIFFRACTION96.9097376612
1.9419-2.03030.1598836221152060.1427354167794205X-RAY DIFFRACTION96.9876868953
2.0303-2.13730.1707903499282350.142394900664170X-RAY DIFFRACTION97.2620887613
2.1373-2.27110.1718879118292190.1426531514124143X-RAY DIFFRACTION96.164021164
2.2711-2.44640.1699274601292110.1534564960984248X-RAY DIFFRACTION97.7207977208
2.4464-2.69240.1805833576872150.1588495110194285X-RAY DIFFRACTION98.3606557377
2.6924-3.08170.1712140878962260.1612582994714286X-RAY DIFFRACTION98.0443285528
3.0817-3.88120.1805929880512230.1503448384914334X-RAY DIFFRACTION98.2112068966
3.8812-29.50240.1619760120672010.1578373126934494X-RAY DIFFRACTION97.1446306642

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