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- PDB-6qgj: Structure of human Bcl-2 in complex with fragment/ABT-263 hybrid -

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Basic information

Entry
Database: PDB / ID: 6qgj
TitleStructure of human Bcl-2 in complex with fragment/ABT-263 hybrid
ComponentsApoptosis regulator Bcl-2,Bcl-2-like protein 1,Apoptosis regulator Bcl-2,Bcl-2-like protein 1
KeywordsAPOPTOSIS / BCL2 / ABT-763 / Drug design
Function / homology
Function and homology information


channel inhibitor activity / negative regulation of cellular pH reduction / negative regulation of retinal cell programmed cell death / pigment granule organization / CD8-positive, alpha-beta T cell lineage commitment / BAD-BCL-2 complex / positive regulation of skeletal muscle fiber development / regulation of glycoprotein biosynthetic process / positive regulation of melanocyte differentiation / melanin metabolic process ...channel inhibitor activity / negative regulation of cellular pH reduction / negative regulation of retinal cell programmed cell death / pigment granule organization / CD8-positive, alpha-beta T cell lineage commitment / BAD-BCL-2 complex / positive regulation of skeletal muscle fiber development / regulation of glycoprotein biosynthetic process / positive regulation of melanocyte differentiation / melanin metabolic process / myeloid cell apoptotic process / cochlear nucleus development / osteoblast proliferation / mesenchymal cell development / retinal cell programmed cell death / positive regulation of neuron maturation / negative regulation of osteoblast proliferation / BH domain binding / gland morphogenesis / apoptotic process in bone marrow cell / renal system process / negative regulation of calcium ion transport into cytosol / regulation of cell-matrix adhesion / ear development / The NLRP1 inflammasome / dendritic cell apoptotic process / SARS-CoV-1-mediated effects on programmed cell death / stem cell development / lymphoid progenitor cell differentiation / dendritic cell proliferation / T cell apoptotic process / positive regulation of mononuclear cell proliferation / melanocyte differentiation / negative regulation of myeloid cell apoptotic process / negative regulation of epithelial cell apoptotic process / BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members / B cell apoptotic process / negative regulation of dendritic cell apoptotic process / negative regulation of T cell apoptotic process / regulation of nitrogen utilization / glomerulus development / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage / metanephros development / positive regulation of multicellular organism growth / Regulation of MITF-M-dependent genes involved in apoptosis / focal adhesion assembly / negative regulation of motor neuron apoptotic process / neuron maturation / negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / regulation of viral genome replication / oocyte development / endoplasmic reticulum calcium ion homeostasis / negative regulation of execution phase of apoptosis / fertilization / regulation of growth / regulation of mitochondrial membrane permeability / response to UV-B / negative regulation of ossification / calcium ion transport into cytosol / response to iron ion / negative regulation of mitochondrial depolarization / Bcl-2 family protein complex / motor neuron apoptotic process / axon regeneration / epithelial cell apoptotic process / smooth muscle cell migration / NFE2L2 regulating tumorigenic genes / intrinsic apoptotic signaling pathway in response to oxidative stress / organ growth / branching involved in ureteric bud morphogenesis / negative regulation of B cell apoptotic process / digestive tract morphogenesis / hair follicle morphogenesis / apoptotic mitochondrial changes / response to cycloheximide / negative regulation of G1/S transition of mitotic cell cycle / B cell lineage commitment / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / STAT5 activation downstream of FLT3 ITD mutants / positive regulation of smooth muscle cell migration / cellular response to alkaloid / hepatocyte apoptotic process / pore complex / negative regulation of release of cytochrome c from mitochondria / negative regulation of reproductive process / negative regulation of developmental process / negative regulation of intrinsic apoptotic signaling pathway / T cell homeostasis / germ cell development / BH3 domain binding / B cell homeostasis / regulation of calcium ion transport / negative regulation of apoptotic signaling pathway / humoral immune response / B cell proliferation / negative regulation of anoikis / extrinsic apoptotic signaling pathway via death domain receptors / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / Activation of BAD and translocation to mitochondria
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
Chem-J1T / Apoptosis regulator Bcl-2 / Bcl-2-like protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9 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)21,4242
Polymers20,4421
Non-polymers9811
Water1,49583
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 area8080 Å2
MethodPISA
Unit cell
Length a, b, c (Å)44.989, 56.173, 64.417
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-J1T / 4-[4-[(1~{R})-1-(6-methoxy-1,3-benzodioxol-5-yl)-2-pyrrolidin-1-yl-ethyl]phenyl]-~{N}-[4-[[(2~{R})-4-morpholin-4-yl-1-phenylsulfanyl-butan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonyl-benzamide


Mass: 981.130 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C48H51F3N4O9S3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 83 / 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: 1.99 Å3/Da / Density % sol: 38.22 %
Crystal growTemperature: 284 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 0.15M KSCN, 20% PEG1500 and 0.1M Na acetate 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: Jun 10, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.75→30 Å / Num. obs: 16972 / % possible obs: 99.1 % / Redundancy: 3.9 % / Rmerge(I) obs: 0.034 / Χ2: 1.14 / Net I/σ(I): 19.5 / Num. measured all: 66248
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
1.75-1.813.80.53916341.193198
1.81-1.893.90.35516751.1921100
1.89-1.9740.24216931.1891100
1.97-2.0740.14816841.1781100
2.07-2.240.10116731.181100
2.2-2.3740.06717071.1271100
2.37-2.6140.04616971.1791100
2.61-2.993.90.03217251.126199.9
2.99-3.773.90.02417460.932199.8
3.77-303.60.0217381.107194.1

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Processing

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

6qgg


Resolution: 1.9→10 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.943 / SU B: 3.477 / SU ML: 0.102 / SU R Cruickshank DPI: 0.1676 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.168 / ESU R Free: 0.142
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2248 616 4.7 %RANDOM
Rwork0.2009 ---
obs0.202 12582 98.63 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 93.82 Å2 / Biso mean: 36.654 Å2 / Biso min: 19.8 Å2
Baniso -1Baniso -2Baniso -3
1-3.47 Å20 Å20 Å2
2---1.25 Å20 Å2
3----2.22 Å2
Refinement stepCycle: final / Resolution: 1.9→10 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1174 0 67 83 1324
Biso mean--45.17 45.07 -
Num. residues----146
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0141293
X-RAY DIFFRACTIONr_bond_other_d0.0010.0171062
X-RAY DIFFRACTIONr_angle_refined_deg1.9031.7191762
X-RAY DIFFRACTIONr_angle_other_deg1.0961.6722408
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0445148
X-RAY DIFFRACTIONr_dihedral_angle_2_deg27.24422.17978
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.74915188
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.895159
X-RAY DIFFRACTIONr_chiral_restr0.080.2148
X-RAY DIFFRACTIONr_gen_planes_refined0.010.021472
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02266
LS refinement shellResolution: 1.9→1.999 Å / Rfactor Rfree error: 0 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.283 95 -
Rwork0.247 1736 -
all-1831 -
obs--100 %

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