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- PDB-6qgh: Structure of human Bcl-2 in complex with ABT-263 -

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Basic information

Entry
Database: PDB / ID: 6qgh
TitleStructure of human Bcl-2 in complex with ABT-263
ComponentsApoptosis regulator Bcl-2,Bcl-2-like protein 1,Apoptosis regulator Bcl-2,Bcl-2-like protein 1
KeywordsAPOPTOSIS / BCL2 / ABT-263 / drug design
Function / homology
Function and homology information


negative regulation of cellular pH reduction / negative regulation of retinal cell programmed cell death / pigment granule organization / channel inhibitor activity / CD8-positive, alpha-beta T cell lineage commitment / BAD-BCL-2 complex / regulation of glycoprotein biosynthetic process / melanin metabolic process / positive regulation of skeletal muscle fiber development / positive regulation of melanocyte differentiation ...negative regulation of cellular pH reduction / negative regulation of retinal cell programmed cell death / pigment granule organization / channel inhibitor activity / CD8-positive, alpha-beta T cell lineage commitment / BAD-BCL-2 complex / regulation of glycoprotein biosynthetic process / melanin metabolic process / positive regulation of skeletal muscle fiber development / positive regulation of melanocyte differentiation / myeloid cell apoptotic process / osteoblast proliferation / cochlear nucleus development / mesenchymal cell development / retinal cell programmed cell death / positive regulation of neuron maturation / negative regulation of osteoblast proliferation / gland morphogenesis / renal system process / apoptotic process in bone marrow cell / regulation of cell-matrix adhesion / T cell apoptotic process / stem cell development / negative regulation of calcium ion transport into cytosol / melanocyte differentiation / SARS-CoV-1-mediated effects on programmed cell death / The NLRP1 inflammasome / dendritic cell apoptotic process / ear development / lymphoid progenitor cell differentiation / dendritic cell proliferation / positive regulation of mononuclear cell proliferation / negative regulation of myeloid cell apoptotic process / negative regulation of epithelial cell apoptotic process / regulation of nitrogen utilization / BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage / B cell apoptotic process / negative regulation of T cell apoptotic process / negative regulation of dendritic cell apoptotic process / glomerulus development / negative regulation of execution phase of apoptosis / oocyte development / positive regulation of multicellular organism growth / metanephros development / neuron maturation / negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / regulation of viral genome replication / negative regulation of motor neuron apoptotic process / focal adhesion assembly / endoplasmic reticulum calcium ion homeostasis / fertilization / negative regulation of ossification / negative regulation of B cell apoptotic process / response to UV-B / regulation of mitochondrial membrane permeability / response to iron ion / negative regulation of protein localization to plasma membrane / regulation of growth / calcium ion transport into cytosol / channel activity / negative regulation of mitochondrial depolarization / motor neuron apoptotic process / Bcl-2 family protein complex / axon regeneration / epithelial cell apoptotic process / smooth muscle cell migration / intrinsic apoptotic signaling pathway in response to oxidative stress / NFE2L2 regulating tumorigenic genes / organ growth / response to cycloheximide / digestive tract morphogenesis / branching involved in ureteric bud morphogenesis / hair follicle morphogenesis / negative regulation of G1/S transition of mitotic cell cycle / : / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / cellular response to alkaloid / STAT5 activation downstream of FLT3 ITD mutants / B cell lineage commitment / pore complex / hepatocyte apoptotic process / positive regulation of smooth muscle cell migration / B cell proliferation / negative regulation of reproductive process / negative regulation of developmental process / negative regulation of release of cytochrome c from mitochondria / BH3 domain binding / T cell homeostasis / germ cell development / apoptotic mitochondrial changes / regulation of calcium ion transport / B cell homeostasis / negative regulation of apoptotic signaling pathway / humoral immune response / negative regulation of anoikis / extrinsic apoptotic signaling pathway via death domain receptors / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress
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 (B-Cell lymphoma); contains BH1, BH2 regions / Bcl-2 family / Bcl-2, Bcl-2 homology region 1-3 / Bcl2-like / Apoptosis regulator proteins, Bcl-2 family / BCL2-like apoptosis inhibitors family profile. / Bcl-2-like superfamily
Similarity search - Domain/homology
Chem-1XJ / Apoptosis regulator Bcl-2 / Bcl-2-like protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2 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 1.3Jan 24, 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

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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)21,4172
Polymers20,4421
Non-polymers9751
Water1,74797
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area8400 Å2
MethodPISA
Unit cell
Length a, b, c (Å)44.419, 55.110, 64.690
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: 20442.461 Da / Num. of mol.: 1
Mutation: H20S, L95Q, R106L, F124G, R127Y, G128A, R129S, 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 BL21 (bacteria) / Variant (production host): pLysS / References: UniProt: P10415, UniProt: Q07817
#2: Chemical ChemComp-1XJ / 4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(2R)-4-(morpholin-4-yl)-1-(phenylsulfanyl)butan-2-yl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl)sulfonyl]benzamide


Mass: 974.613 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C47H55ClF3N5O6S3 / Feature type: SUBJECT OF INVESTIGATION / Comment: anticancer, inhibitor*YM
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 97 / 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: 1.94 Å3/Da / Density % sol: 36.49 %
Crystal growTemperature: 284 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 0.2 M NaCl, 25% PEG3350 and 0.1 M Bis-Tris buffer pH 5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Aug 29, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.9→27.9 Å / Num. obs: 12847 / % possible obs: 98 % / Redundancy: 4.62 % / Rmerge(I) obs: 0.103 / Rrim(I) all: 0.103 / Χ2: 0.96 / Net I/σ(I): 8.1 / Num. measured all: 59783 / Scaling rejects: 450
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsΧ2% possible all
1.9-1.974.20.4712.811711.3890.8
1.97-2.044.70.4083.112401.1697.5
2.04-2.144.670.3593.412671.1198.4
2.14-2.254.670.2954.112671.0298.5
2.25-2.394.680.231512760.9198.7
2.39-2.584.680.2045.712800.9399.2
2.58-2.834.680.1497.113060.8899.4
2.83-3.244.680.110.713120.8399.8
3.24-4.094.680.05816.113320.7299.8
4.09-27.94.530.04720.513960.7297.8

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Processing

Software
NameVersionClassification
d*TREK9.4SSIdata scaling
REFMAC5.8.0230refinement
PDB_EXTRACT3.24data extraction
CrystalCleardata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6qgg

6qgg


Resolution: 2→20 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.947 / SU B: 4.562 / SU ML: 0.121 / SU R Cruickshank DPI: 0.1951 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.195 / ESU R Free: 0.154
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2057 507 4.6 %RANDOM
Rwork0.1774 ---
obs0.1787 10574 98.75 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 77.75 Å2 / Biso mean: 29.571 Å2 / Biso min: 15.55 Å2
Baniso -1Baniso -2Baniso -3
1-1.49 Å2-0 Å20 Å2
2---0.49 Å20 Å2
3----1 Å2
Refinement stepCycle: final / Resolution: 2→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1242 0 65 97 1404
Biso mean--25.14 35.15 -
Num. residues----154
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0141363
X-RAY DIFFRACTIONr_bond_other_d0.0010.0181141
X-RAY DIFFRACTIONr_angle_refined_deg1.4691.6051859
X-RAY DIFFRACTIONr_angle_other_deg1.0071.6292589
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5185160
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.56421.68783
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.29415205
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.0471511
X-RAY DIFFRACTIONr_chiral_restr0.0720.2158
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.021559
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02279
LS refinement shellResolution: 2→2.107 Å / Rfactor Rfree error: 0 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.314 75 -
Rwork0.267 1480 -
all-1555 -
obs--97.92 %

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