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- PDB-6qgk: Structure of human Bcl-2 in complex with THIQ-phenyl pyrazole compound -

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Basic information

Entry
Database: PDB / ID: 6qgk
TitleStructure of human Bcl-2 in complex with THIQ-phenyl pyrazole compound
ComponentsApoptosis regulator Bcl-2,Bcl-2-like protein 1,Apoptosis regulator Bcl-2,Bcl-2-like protein 1
KeywordsAPOPTOSIS / BCL2 / drug design / small molecule inhibitor
Function / homology
Function and homology information


: / channel inhibitor activity / dendritic cell apoptotic process / dendritic cell proliferation / apoptotic process in bone marrow cell / The NLRP1 inflammasome / positive regulation of mononuclear cell proliferation / SARS-CoV-1-mediated effects on programmed cell death / negative regulation of dendritic cell apoptotic process / BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members ...: / channel inhibitor activity / dendritic cell apoptotic process / dendritic cell proliferation / apoptotic process in bone marrow cell / The NLRP1 inflammasome / positive regulation of mononuclear cell proliferation / SARS-CoV-1-mediated effects on programmed cell death / negative regulation of dendritic cell apoptotic process / BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage / fertilization / hair follicle morphogenesis / negative regulation of execution phase of apoptosis / pigmentation / negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / regulation of viral genome replication / endoplasmic reticulum calcium ion homeostasis / Regulation of MITF-M-dependent genes involved in apoptosis / regulation of growth / regulation of mitochondrial membrane permeability / germ cell development / apoptotic mitochondrial changes / response to iron ion / negative regulation of mitochondrial depolarization / Bcl-2 family protein complex / NFE2L2 regulating tumorigenic genes / hepatocyte apoptotic process / response to cycloheximide / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / STAT5 activation downstream of FLT3 ITD mutants / cellular response to alkaloid / negative regulation of release of cytochrome c from mitochondria / negative regulation of intrinsic apoptotic signaling pathway / humoral immune response / extrinsic apoptotic signaling pathway via death domain receptors / B cell proliferation / pore complex / regulation of calcium ion transport / negative regulation of reproductive process / negative regulation of developmental process / ectopic germ cell programmed cell death / negative regulation of apoptotic signaling pathway / negative regulation of anoikis / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / BH3 domain binding / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / Activation of BAD and translocation to mitochondria / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / extrinsic apoptotic signaling pathway in absence of ligand / epithelial cell proliferation / ovarian follicle development / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / negative regulation of protein localization to plasma membrane / negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / positive regulation of B cell proliferation / response to cytokine / release of cytochrome c from mitochondria / male gonad development / negative regulation of autophagy / regulation of mitochondrial membrane potential / protein phosphatase 2A binding / B cell receptor signaling pathway / cellular response to amino acid stimulus / regulation of cytokinesis / intrinsic apoptotic signaling pathway in response to DNA damage / response to nicotine / myelin sheath / female pregnancy / in utero embryonic development / cellular response to gamma radiation / response to radiation / response to toxic substance / neuron apoptotic process / endocytosis / autophagy / protein polyubiquitination / RAS processing / positive regulation of cell growth / synaptic vesicle membrane / nuclear membrane / channel activity / protease binding / Interleukin-4 and Interleukin-13 signaling / spermatogenesis / negative regulation of neuron apoptotic process / Estrogen-dependent gene expression / DNA-binding transcription factor binding / defense response to virus / sequence-specific DNA binding / molecular adaptor activity / mitochondrial outer membrane / mitochondrial inner membrane / response to xenobiotic stimulus / positive regulation of apoptotic process / mitochondrial matrix / protein heterodimerization activity / positive regulation of cell population proliferation / centrosome / ubiquitin protein ligase binding
Similarity search - Function
Apoptosis regulator, Bcl-2 / 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. / 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 / Apoptosis regulator, Bcl-2, BH3 motif, conserved site ...Apoptosis regulator, Bcl-2 / 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. / 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 / 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
Similarity search - Domain/homology
ACETATE ION / Chem-J1Q / Apoptosis regulator Bcl-2 / Bcl-2-like protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsDokurno, P. / Murray, J. / Davidson, J. / Chen, I. / Davis, B. / Graham, C.J. / Harris, R. / Jordan, A.M. / Matassova, N. / Pedder, C. ...Dokurno, P. / Murray, J. / Davidson, J. / Chen, I. / Davis, B. / Graham, C.J. / Harris, R. / Jordan, A.M. / Matassova, N. / Pedder, C. / Ray, S. / Roughley, S. / Smith, J. / Walmsley, C. / Wang, Y. / Whitehead, N. / Williamson, D.S. / Casara, P. / Le Diguarher, T. / Hickman, J. / Stark, J. / Kotschy, A. / Geneste, O. / Hubbard, R.E.
CitationJournal: Acs Omega / Year: 2019
Title: Establishing Drug Discovery and Identification of Hit Series for the Anti-apoptotic Proteins, Bcl-2 and Mcl-1.
Authors: Murray, J.B. / Davidson, J. / Chen, I. / Davis, B. / Dokurno, P. / Graham, C.J. / Harris, R. / Jordan, A. / Matassova, N. / Pedder, C. / Ray, S. / Roughley, S.D. / Smith, J. / Walmsley, C. / ...Authors: Murray, J.B. / Davidson, J. / Chen, I. / Davis, B. / Dokurno, P. / Graham, C.J. / Harris, R. / Jordan, A. / Matassova, N. / Pedder, C. / Ray, S. / Roughley, S.D. / Smith, J. / Walmsley, C. / Wang, Y. / Whitehead, N. / Williamson, D.S. / Casara, P. / Le Diguarher, T. / Hickman, J. / Stark, J. / Kotschy, A. / Geneste, O. / Hubbard, R.E.
History
DepositionJan 11, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 12, 2019Provider: repository / Type: Initial release
Revision 1.1Sep 11, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Sep 18, 2019Group: Data collection / Refinement description / Category: software / Item: _software.version
Revision 1.3May 15, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Apoptosis regulator Bcl-2,Bcl-2-like protein 1,Apoptosis regulator Bcl-2,Bcl-2-like protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,8863
Polymers20,3251
Non-polymers5612
Water2,810156
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area150 Å2
ΔGint1 kcal/mol
Surface area8170 Å2
MethodPISA
Unit cell
Length a, b, c (Å)47.570, 50.104, 65.371
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 20325.404 Da / Num. of mol.: 1
Mutation: H20S, E42A, E44A, L95Q, R106L, E114Q, F124G, R127Y, G128A, R129S, E135A, E165A, P168V, L175A, T178A, E179T, R183D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BCL2, BCL2L1, BCL2L, BCLX / Production host: Escherichia coli (E. coli) / References: UniProt: P10415, UniProt: Q07817
#2: Chemical ChemComp-J1Q / 1-[2-[[(3~{S})-3-(aminomethyl)-3,4-dihydro-1~{H}-isoquinolin-2-yl]carbonyl]phenyl]-~{N},~{N}-dibutyl-5-methyl-pyrazole-3-carboxamide


Mass: 501.663 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H39N5O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 156 / 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: 1.93 Å3/Da / Density % sol: 36.18 %
Crystal growTemperature: 284 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.2M Ca Acetate, 15% PEG4k, 0.1M Tris buffer pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9728 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Dec 12, 2008
RadiationMonochromator: mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9728 Å / Relative weight: 1
ReflectionResolution: 1.7→25 Å / Num. obs: 14748 / % possible obs: 82.8 % / Redundancy: 4.4 % / Rmerge(I) obs: 0.071 / Χ2: 1.076 / Net I/σ(I): 10.7 / Num. measured all: 64967
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
1.7-1.763.90.367940.881145.2
1.76-1.834.10.30810470.969160.4
1.83-1.914.30.28913471.043177.1
1.91-2.024.40.23115491.155188.4
2.02-2.144.50.1916621.195194.8
2.14-2.314.50.13817011.159196.4
2.31-2.544.50.10516741.086194.7
2.54-2.914.50.08916231.046190.2
2.91-3.664.50.06416051.032188.4
3.66-254.50.03717461.028191.1

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
REFMAC5.8.0230refinement
PDB_EXTRACT3.24data extraction
DENZOdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→15 Å / Cor.coef. Fo:Fc: 0.968 / Cor.coef. Fo:Fc free: 0.955 / SU B: 3.007 / SU ML: 0.09 / SU R Cruickshank DPI: 0.1365 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.137 / ESU R Free: 0.126
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2021 613 4.6 %RANDOM
Rwork0.1655 ---
obs0.1673 12725 88.74 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 96.3 Å2 / Biso mean: 29.485 Å2 / Biso min: 15.21 Å2
Baniso -1Baniso -2Baniso -3
1-2.74 Å2-0 Å20 Å2
2---2.4 Å2-0 Å2
3----0.33 Å2
Refinement stepCycle: final / Resolution: 1.8→15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1157 0 41 156 1354
Biso mean--21.84 40.65 -
Num. residues----148
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0141241
X-RAY DIFFRACTIONr_bond_other_d0.0010.0181048
X-RAY DIFFRACTIONr_angle_refined_deg1.451.6781687
X-RAY DIFFRACTIONr_angle_other_deg1.0631.7062426
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.8695150
X-RAY DIFFRACTIONr_dihedral_angle_2_deg29.63121.54971
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.23115176
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.415159
X-RAY DIFFRACTIONr_chiral_restr0.0750.2150
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.021446
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02271
LS refinement shellResolution: 1.8→1.896 Å / Rfactor Rfree error: 0 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.233 66 -
Rwork0.228 1453 -
all-1519 -
obs--71.82 %

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