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- PDB-2mej: Solution Structure of the Complex Between BCL-xL and the p53 Core... -

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Basic information

Entry
Database: PDB / ID: 2mej
TitleSolution Structure of the Complex Between BCL-xL and the p53 Core Domain determined with PRE restraints
Components
  • Bcl-2-like protein 1
  • Cellular tumor antigen p53
KeywordsAPOPTOSIS / BCL-xL / p53 / BCL-2 family / cytoplasmic p53 / selective labeling
Function / homology
Function and homology information


apoptotic process in bone marrow cell / The NLRP1 inflammasome / dendritic cell apoptotic process / SARS-CoV-1-mediated effects on programmed cell death / dendritic cell proliferation / positive regulation of mononuclear cell proliferation / BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members / negative regulation of dendritic cell apoptotic process / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage / negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway ...apoptotic process in bone marrow cell / The NLRP1 inflammasome / dendritic cell apoptotic process / SARS-CoV-1-mediated effects on programmed cell death / dendritic cell proliferation / positive regulation of mononuclear cell proliferation / BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members / negative regulation of dendritic cell apoptotic process / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage / negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / negative regulation of execution phase of apoptosis / Loss of function of TP53 in cancer due to loss of tetramerization ability / Regulation of TP53 Expression / fertilization / negative regulation of helicase activity / 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 / intrinsic apoptotic signaling pathway in response to hypoxia / regulation of growth / oligodendrocyte apoptotic process / negative regulation of miRNA processing / positive regulation of thymocyte apoptotic process / oxidative stress-induced premature senescence / regulation of tissue remodeling / glucose catabolic process to lactate via pyruvate / positive regulation of mitochondrial membrane permeability / regulation of mitochondrial membrane permeability / positive regulation of programmed necrotic cell death / mRNA transcription / bone marrow development / circadian behavior / regulation of mitochondrial membrane permeability involved in apoptotic process / germ cell nucleus / RUNX3 regulates CDKN1A transcription / 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 / Bcl-2 family protein complex / regulation of DNA damage response, signal transduction by p53 class mediator / histone deacetylase regulator activity / negative regulation of glial cell proliferation / NFE2L2 regulating tumorigenic genes / Regulation of TP53 Activity through Association with Co-factors / negative regulation of neuroblast proliferation / T cell lineage commitment / mitochondrial DNA repair / apoptotic mitochondrial changes / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / ER overload response / response to cycloheximide / STAT5 activation downstream of FLT3 ITD mutants / B cell lineage commitment / cellular response to alkaloid / thymocyte apoptotic process / hepatocyte apoptotic process / TP53 Regulates Transcription of Caspase Activators and Caspases / negative regulation of mitophagy / cardiac septum morphogenesis / negative regulation of DNA replication / entrainment of circadian clock by photoperiod / PI5P Regulates TP53 Acetylation / negative regulation of release of cytochrome c from mitochondria / negative regulation of reproductive process / negative regulation of developmental process / negative regulation of telomere maintenance via telomerase / negative regulation of intrinsic apoptotic signaling pathway / Zygotic genome activation (ZGA) / positive regulation of release of cytochrome c from mitochondria / Association of TriC/CCT with target proteins during biosynthesis / necroptotic process / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / germ cell development / BH3 domain binding / rRNA transcription / 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 / T cell proliferation involved in immune response / negative regulation of reactive oxygen species metabolic process / negative regulation of anoikis / positive regulation of execution phase of apoptosis / Transcriptional Regulation by VENTX / replicative senescence / cellular response to UV-C / general transcription initiation factor binding / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / cellular response to actinomycin D / neuroblast proliferation / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of RNA polymerase II transcription preinitiation complex assembly / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator
Similarity search - Function
Apoptosis regulator, Bcl-X / Apoptosis regulator, Bcl-2/ BclX / Apoptosis regulator, Bcl-2, BH4 motif, conserved site / Apoptosis regulator, Bcl-2 family BH4 motif signature. / Immunoglobulin-like - #720 / Apoptosis regulator, Bcl-2 protein, BH4 / Bcl-2 homology region 4 / Apoptosis regulator, Bcl-2 family BH4 motif profile. / BH4 Bcl-2 homology region 4 / Blc2-like ...Apoptosis regulator, Bcl-X / Apoptosis regulator, Bcl-2/ BclX / Apoptosis regulator, Bcl-2, BH4 motif, conserved site / Apoptosis regulator, Bcl-2 family BH4 motif signature. / Immunoglobulin-like - #720 / Apoptosis regulator, Bcl-2 protein, BH4 / Bcl-2 homology region 4 / Apoptosis regulator, Bcl-2 family BH4 motif profile. / BH4 Bcl-2 homology region 4 / Blc2-like / Apoptosis Regulator Bcl-x / 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 / Apoptosis regulator, Bcl-2, BH3 motif, conserved site / Apoptosis regulator, Bcl-2 family BH3 motif signature. / Apoptosis regulator, Bcl-2, BH1 motif, conserved site / Apoptosis regulator, Bcl-2 family BH1 motif signature. / Apoptosis regulator, Bcl-2, BH2 motif, conserved site / Apoptosis regulator, Bcl-2 family BH2 motif signature. / Bcl-2 family / BCL (B-Cell lymphoma); contains BH1, BH2 regions / Bcl2-like / Bcl-2, Bcl-2 homology region 1-3 / Apoptosis regulator proteins, Bcl-2 family / BCL2-like apoptosis inhibitors family profile. / Bcl-2-like superfamily / p53-like transcription factor, DNA-binding / Immunoglobulin-like / Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Cellular tumor antigen p53 / Bcl-2-like protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodSOLUTION NMR / molecular dynamics
AuthorsViacava Follis, A. / Grace, C.R. / Kriwacki, R.W.
CitationJournal: Nat.Struct.Mol.Biol. / Year: 2014
Title: The DNA-binding domain mediates both nuclear and cytosolic functions of p53.
Authors: Follis, A.V. / Llambi, F. / Ou, L. / Baran, K. / Green, D.R. / Kriwacki, R.W.
History
DepositionSep 25, 2013Deposition site: BMRB / Processing site: RCSB
Revision 1.0Apr 30, 2014Provider: repository / Type: Initial release
Revision 1.1Jul 9, 2014Group: Database references
Revision 1.2Apr 27, 2016Group: Structure summary
Revision 1.3Jun 14, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: database_2 / pdbx_database_status ...database_2 / pdbx_database_status / pdbx_nmr_software / pdbx_nmr_spectrometer / struct_ref_seq_dif / 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_nmr_data / _pdbx_nmr_software.name / _pdbx_nmr_spectrometer.model / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4May 15, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2 / Item: _database_2.pdbx_DOI

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Bcl-2-like protein 1
B: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,1483
Polymers48,0832
Non-polymers651
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
NMR ensembles
DataCriteria
Number of conformers (submitted / calculated)20 / 200structures with the lowest energy
RepresentativeModel #1lowest energy

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Components

#1: Protein Bcl-2-like protein 1 / Bcl2-L-1 / Apoptosis regulator Bcl-X


Mass: 23669.945 Da / Num. of mol.: 1 / Fragment: UNP residues 1-209
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BCL2L1, BCL2L, BCLX / Plasmid: pET28 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q07817
#2: Protein Cellular tumor antigen p53 / Antigen NY-CO-13 / Phosphoprotein p53 / Tumor suppressor p53


Mass: 24412.721 Da / Num. of mol.: 1 / Fragment: UNP residues 96-312
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TP53, P53 / Plasmid: pET28 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P04637
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn

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Experimental details

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Experiment

ExperimentMethod: SOLUTION NMR
Details: SOLUTION STRUCTURE OF THE KINETICALLY LABILE COMPLEX BETWEEN THE DNA BINDING DOMAIN OF P53 AND BCL-XL DETERMINED USING PARAMAGNETIC RELAXATION ENHANCEMENT AND LIMITED NOE CONSTRAINTS
NMR experiment
Conditions-IDExperiment-IDSolution-IDType
1112D 1H-15N HSQC
1222D 1H-15N HSQC
1332D 1H-15N HSQC
1442D 1H-15N HSQC
1552D 1H-15N HSQC
1652D 1H-15N HSQC
1772D 1H-15N HSQC
1882D 1H-15N HSQC
1992D 1H-15N HSQC
110102D 1H-15N HSQC
11123D 1H-15N NOESY
11213D HNCA
11313D HN(CA)CB
11413D HNCO
11513D HN(CO)CA
11612D 1H-13C HSQC aliphatic
11713D (H)CCH-TOCSY
11813D 1H-13C NOESY aliphatic
11922D 1H-13C HSQC aliphatic
12092D CBCACO
121102D CBCACO
12292D 1H-13C HSQC aliphatic
123102D 1H-13C HSQC aliphatic
NMR detailsText: HADDOCK STARTING STRUCTURES: FOR CHAIN A (BCL-XL), THE LOWEST ENERGY CONFORMER OF PDB ENTRY 2ME8 DEPOSITED BY THE AUTHORS; FOR CHAIN B (P53 DNA BINDING DOMAIN), CHAIN C OF PDB ENTRY 2AC0, THE P53 CRYSTAL STRUCTURE.

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Sample preparation

Details
Solution-IDContentsSolvent system
10.6 mM [U-98% 13C; U-98% 15N; U-98% 2H] p53, 93% H2O/7% D2O93% H2O/7% D2O
20.6 mM [U-98% 13C; U-98% 15N; U-98% 2H] p53, 0.65 mM BCL-xL, 93% H2O/7% D2O93% H2O/7% D2O
30.1 mM [U-98% 15N; U-98% 2H] p53, 0.1 mM BCL-xL_C151MTSL, 93% H2O/7% D2O93% H2O/7% D2O
40.1 mM [U-98% 15N; U-98% 2H] p53, 0.1 mM BCL-xL_C151MTSL, 93% H2O/7% D2O93% H2O/7% D2O
50.1 mM [U-98% 15N; U-98% 2H] p53, 0.1 mM BCL-xL_C151S_S122C MTSL, 93% H2O/7% D2O93% H2O/7% D2O
60.1 mM [U-98% 15N; U-98% 2H] p53, 0.1 mM BCL-xL_C151S_S122C MTSL, 93% H2O/7% D2O93% H2O/7% D2O
70.1 mM [U-98% 15N; U-98% 2H] p53, 0.1 mM BCL-xL_C151S_S2C MTSL, 93% H2O/7% D2O93% H2O/7% D2O
80.1 mM [U-98% 15N; U-98% 2H] p53, 0.1 mM BCL-xL_C151S_S2C MTSL, 93% H2O/7% D2O93% H2O/7% D2O
90.1 mM [U-98% 15N; U-98% 2H] BCL-xL, 0.1 mM Co_p53, 93% H2O/7% D2O93% H2O/7% D2O
100.1 mM [U-98% 15N; U-98% 2H] BCL-xL, 0.1 mM p53, 93% H2O/7% D2O93% H2O/7% D2O
Sample
Conc. (mg/ml)ComponentIsotopic labelingSolution-ID
0.6 mMp53-1[U-98% 13C; U-98% 15N; U-98% 2H]1
0.6 mMp53-2[U-98% 13C; U-98% 15N; U-98% 2H]2
0.65 mMBCL-xL-32
0.1 mMp53-4[U-98% 15N; U-98% 2H]3
0.1 mMBCL-xL_C151MTSL-53
0.1 mMp53-6[U-98% 15N; U-98% 2H]4
0.1 mMBCL-xL_C151MTSL-74
0.1 mMp53-8[U-98% 15N; U-98% 2H]5
0.1 mMBCL-xL_C151S_S122C MTSL-95
0.1 mMp53-10[U-98% 15N; U-98% 2H]6
0.1 mMBCL-xL_C151S_S122C MTSL-116
0.1 mMp53-12[U-98% 15N; U-98% 2H]7
0.1 mMBCL-xL_C151S_S2C MTSL-137
0.1 mMp53-14[U-98% 15N; U-98% 2H]8
0.1 mMBCL-xL_C151S_S2C MTSL-158
0.1 mMBCL-xL-16[U-98% 15N; U-98% 2H]9
0.1 mMCo_p53-179
0.1 mMBCL-xL-18[U-98% 15N; U-98% 2H]10
0.1 mMp53-1910
Sample conditionsIonic strength: 0.05 / pH: 7 / Pressure: ambient / Temperature: 298 K

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NMR measurement

NMR spectrometer
TypeManufacturerModelField strength (MHz)Spectrometer-ID
Bruker AvanceBrukerAVANCE8001
Bruker AvanceBrukerAVANCE6002

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Processing

NMR software
NameVersionDeveloperClassification
TopSpin2.1Bruker Biospincollection
TopSpin2.1Bruker Biospinprocessing
CARAKeller, R.L.J.data analysis
CARAKeller, R.L.J.chemical shift assignment
HADDOCKBonvin, A.structure solution
AmberCase, Darden, Cheatham, III, Simmerling, Wang, Duke, Luo, ... and Kollmanrefinement
RefinementMethod: molecular dynamics / Software ordinal: 1
Details: ENERGY MINIMIZATION WITH 100 STEPS STEEPEST GRADIENT DESCENT FOLLOWED BY 100 CONJUGATE GRADIENT DESCENT STEPS
NMR constraintsNOE constraints total: 13 / NOE intraresidue total count: 0 / NOE long range total count: 13 / NOE medium range total count: 0 / NOE sequential total count: 0 / Hydrogen bond constraints total count: 0 / Protein chi angle constraints total count: 0 / Protein other angle constraints total count: 0 / Protein phi angle constraints total count: 0 / Protein psi angle constraints total count: 0
NMR representativeSelection criteria: lowest energy
NMR ensembleConformer selection criteria: structures with the lowest energy
Conformers calculated total number: 200 / Conformers submitted total number: 20 / Maximum lower distance constraint violation: 0 Å / Maximum upper distance constraint violation: 1.39 Å
NMR ensemble rmsDistance rms dev: 0.13 Å / Distance rms dev error: 0.06 Å

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