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- PDB-6o0k: crystal structure of BCL-2 with venetoclax -

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Basic information

Entry
Database: PDB / ID: 6o0k
Titlecrystal structure of BCL-2 with venetoclax
ComponentsApoptosis regulator Bcl-2
KeywordsAPOPTOSIS / BCL-2 / Venetoclax / complex / Protein-protein interface inhibitor / FDA approved drug complex
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 / T cell apoptotic process / regulation of cell-matrix adhesion / stem cell development / negative regulation of calcium ion transport into cytosol / melanocyte differentiation / ear development / The NLRP1 inflammasome / SARS-CoV-1-mediated effects on programmed cell death / dendritic cell apoptotic process / 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 / B cell apoptotic process / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage / glomerulus development / negative regulation of T cell apoptotic process / negative regulation of dendritic cell apoptotic process / oocyte development / neuron maturation / positive regulation of multicellular organism growth / negative regulation of execution phase of apoptosis / metanephros development / negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / regulation of viral genome replication / focal adhesion assembly / negative regulation of motor neuron apoptotic process / endoplasmic reticulum calcium ion homeostasis / negative regulation of ossification / fertilization / negative regulation of B cell apoptotic process / response to UV-B / response to iron ion / negative regulation of protein localization to plasma membrane / negative regulation of mitochondrial depolarization / regulation of mitochondrial membrane permeability / regulation of growth / calcium ion transport into cytosol / epithelial cell apoptotic process / channel activity / motor neuron apoptotic process / axon regeneration / Bcl-2 family protein complex / smooth muscle cell migration / intrinsic apoptotic signaling pathway in response to oxidative stress / organ growth / NFE2L2 regulating tumorigenic genes / digestive tract morphogenesis / response to cycloheximide / cellular response to organic substance / 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 / B cell lineage commitment / STAT5 activation downstream of FLT3 ITD mutants / 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 / T cell homeostasis / BH3 domain binding / apoptotic mitochondrial changes / germ cell development / regulation of calcium ion transport / negative regulation of apoptotic signaling pathway / B cell homeostasis / 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 / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / Estrogen-dependent nuclear events downstream of ESR-membrane signaling
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-LBM / Apoptosis regulator Bcl-2 / Bcl-2-like protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.62 Å
AuthorsBirkinshaw, R.W. / Luo, C.S. / Colman, P.M. / Czabotar, P.E.
CitationJournal: Nat Commun / Year: 2019
Title: Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations.
Authors: Birkinshaw, R.W. / Gong, J.N. / Luo, C.S. / Lio, D. / White, C.A. / Anderson, M.A. / Blombery, P. / Lessene, G. / Majewski, I.J. / Thijssen, R. / Roberts, A.W. / Huang, D.C.S. / Colman, P.M. / Czabotar, P.E.
History
DepositionFeb 16, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 22, 2019Provider: repository / Type: Initial release
Revision 1.1Jun 19, 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 1.2Jul 10, 2019Group: Data collection / Database references ...Data collection / Database references / Source and taxonomy / Structure summary
Category: entity_name_com / entity_src_gen ...entity_name_com / entity_src_gen / struct_ref / struct_ref_seq
Revision 2.0Nov 20, 2019Group: Derived calculations / Non-polymer description / Structure summary
Category: chem_comp / entity / pdbx_entity_nonpoly
Item: _chem_comp.formula / _chem_comp.formula_weight ..._chem_comp.formula / _chem_comp.formula_weight / _chem_comp.name / _entity.formula_weight / _entity.pdbx_description / _pdbx_entity_nonpoly.name
Revision 2.1Dec 11, 2019Group: Structure summary / Category: chem_comp / Item: _chem_comp.pdbx_synonyms
Revision 2.2Oct 11, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / entity / pdbx_entity_nonpoly / pdbx_initial_refinement_model
Item: _chem_comp.name / _chem_comp.pdbx_synonyms ..._chem_comp.name / _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_entity_nonpoly.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Apoptosis regulator Bcl-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,6403
Polymers19,3581
Non-polymers1,2832
Water1,76598
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)33.725, 48.506, 87.316
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 19357.557 Da / Num. of mol.: 1
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) / Strain (production host): BL21 / References: UniProt: P10415, UniProt: Q07817
#2: Chemical ChemComp-LBM / 4-{4-[(4'-chloro-5,5-dimethyl[3,4,5,6-tetrahydro[1,1'-biphenyl]]-2-yl)methyl]piperazin-1-yl}-N-[(3-nitro-4-{[(oxan-4-yl )methyl]amino}phenyl)sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide / Venetoclax, 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)pipe razin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide / Venetoclax


Mass: 868.439 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C45H50ClN7O7S / Comment: medication*YM
#3: Chemical ChemComp-2PE / NONAETHYLENE GLYCOL / Polyethylene glycol


Mass: 414.488 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H38O10 / Comment: precipitant*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 98 / 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: 1.84 Å3/Da / Density % sol: 33.32 %
Crystal growTemperature: 291 K / Method: vapor diffusion / pH: 6 / Details: 5% PEG4K, 40%PEG400, 0.1M MES pH 6.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.9537 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Nov 30, 2016
RadiationMonochromator: Double-crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 1.62→43.658 Å / Num. obs: 18474 / % possible obs: 97.77 % / Redundancy: 7 % / Biso Wilson estimate: 15.5 Å2 / CC1/2: 0.998 / Rrim(I) all: 0.1054 / Net I/σ(I): 12.57
Reflection shellResolution: 1.62→1.68 Å / Redundancy: 5.5 % / Mean I/σ(I) obs: 2.16 / Num. unique obs: 1508 / CC1/2: 0.604 / % possible all: 80.73

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Processing

Software
NameVersionClassification
PHENIX(1.14_3260: ???)refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4LVT

4lvt


Resolution: 1.62→43.658 Å / SU ML: 0.18 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 19.98 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2024 905 4.9 %
Rwork0.1612 --
obs0.1632 18463 97.77 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.62→43.658 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1172 0 89 98 1359
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.021466
X-RAY DIFFRACTIONf_angle_d1.5121998
X-RAY DIFFRACTIONf_dihedral_angle_d19.16900
X-RAY DIFFRACTIONf_chiral_restr0.114186
X-RAY DIFFRACTIONf_plane_restr0.01322
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.62-1.72150.26141310.21812559X-RAY DIFFRACTION88
1.7215-1.85450.22741490.18432942X-RAY DIFFRACTION100
1.8545-2.04110.20221460.15412947X-RAY DIFFRACTION100
2.0411-2.33640.19921540.142956X-RAY DIFFRACTION100
2.3364-2.94360.20091560.15683003X-RAY DIFFRACTION100
2.9436-43.67380.19151690.16163151X-RAY DIFFRACTION100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.02380.4526-0.07644.27632.05733.6595-0.0405-0.1932-0.15060.28730.0573-0.13680.27830.18380.03720.11860.009-0.00280.11630.00520.12272.9883-4.6853-8.4132
24.03520.5373-0.09433.53220.665.16020.01960.146-0.1527-0.14880.04690.11540.23850.0319-0.12460.113-0.00390.01520.0866-0.01620.1444-10.5218-3.8155-11.8456
33.3062-1.0961-1.66123.34340.90034.43420.11380.41730.206-0.3757-0.0822-0.0662-0.0388-0.18740.08070.15270.01620.00120.08660.03290.1267-5.38288.7284-20.3167
42.3012-0.5555-1.42231.95971.15542.3084-0.0069-0.08210.07480.03160.0345-0.06270.0850.0664-0.01640.10090.0113-0.01320.087-0.0020.0884-2.57585.1764-9.515
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 9 through 90 )
2X-RAY DIFFRACTION2chain 'A' and (resid 91 through 118 )
3X-RAY DIFFRACTION3chain 'A' and (resid 119 through 143 )
4X-RAY DIFFRACTION4chain 'A' and (resid 144 through 203 )

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