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- PDB-6o0p: crystal structure of BCL-2 G101A mutation with venetoclax -

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Basic information

Entry
Database: PDB / ID: 6o0p
Titlecrystal structure of BCL-2 G101A mutation with venetoclax
ComponentsApoptosis regulator Bcl-2,Bcl-2-like protein 1,Apoptosis regulator Bcl-2
KeywordsAPOPTOSIS / BCL-2 / Venetoclax / complex / Protein-protein interface inhibitor / FDA approved drug complex
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 / negative regulation of execution phase of apoptosis / negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / pigmentation / regulation of viral genome replication / endoplasmic reticulum calcium ion homeostasis / hair follicle morphogenesis / fertilization / Regulation of MITF-M-dependent genes involved in apoptosis / regulation of growth / regulation of mitochondrial membrane permeability / response to iron ion / apoptotic mitochondrial changes / negative regulation of mitochondrial depolarization / germ cell development / 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 / extrinsic apoptotic signaling pathway via death domain receptors / negative regulation of intrinsic apoptotic signaling pathway / pore complex / humoral immune response / B cell proliferation / regulation of calcium ion transport / negative regulation of reproductive process / negative regulation of developmental process / negative regulation of anoikis / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / ectopic germ cell programmed cell death / BH3 domain binding / negative regulation of apoptotic signaling pathway / Activation of BAD and translocation to mitochondria / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / epithelial cell proliferation / negative regulation of protein localization to plasma membrane / ovarian follicle development / negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of B cell proliferation / response to cytokine / release of cytochrome c from mitochondria / protein phosphatase 2A binding / regulation of mitochondrial membrane potential / negative regulation of autophagy / B cell receptor signaling pathway / cellular response to amino acid stimulus / regulation of cytokinesis / response to nicotine / female pregnancy / male gonad development / cellular response to gamma radiation / response to radiation / intrinsic apoptotic signaling pathway in response to DNA damage / response to toxic substance / endocytosis / autophagy / protein polyubiquitination / RAS processing / in utero embryonic development / neuron apoptotic process / myelin sheath / synaptic vesicle membrane / channel activity / positive regulation of cell growth / nuclear membrane / protease binding / Interleukin-4 and Interleukin-13 signaling / spermatogenesis / Estrogen-dependent gene expression / DNA-binding transcription factor binding / sequence-specific DNA binding / negative regulation of neuron apoptotic process / defense response to virus / molecular adaptor activity / mitochondrial outer membrane / mitochondrial inner membrane / response to xenobiotic stimulus / positive regulation of apoptotic process / mitochondrial matrix / protein heterodimerization activity / centrosome / positive regulation of cell population proliferation / apoptotic process
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-LBM / DI(HYDROXYETHYL)ETHER / 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
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 17, 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 / entity_name_com ...entity / entity_name_com / entity_src_gen / struct_ref / struct_ref_seq / struct_ref_seq_dif
Item: _entity.pdbx_description / _entity.pdbx_mutation
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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)20,5585
Polymers19,3721
Non-polymers1,1874
Water64936
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)33.398, 48.945, 86.474
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,Bcl-2-like protein 1,Apoptosis regulator Bcl-2 / Bcl2-L-1 / Apoptosis regulator Bcl-X


Mass: 19371.584 Da / Num. of mol.: 1 / Mutation: G101A,G101A,G101A
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): 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


Mass: 868.439 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C45H50ClN7O7S
#3: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C4H10O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 36 / 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: 1.82 Å3/Da / Density % sol: 32.58 %
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: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Aug 25, 2018
RadiationMonochromator: Double-crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 1.8→43.24 Å / Num. obs: 13559 / % possible obs: 98.45 % / Redundancy: 6.1 % / Biso Wilson estimate: 30.55 Å2 / CC1/2: 0.997 / Rrim(I) all: 0.1129 / Net I/σ(I): 9.56
Reflection shellResolution: 1.8→1.864 Å / Redundancy: 4.2 % / Mean I/σ(I) obs: 0.82 / Num. unique obs: 1200 / CC1/2: 0.292 / Rrim(I) all: 2.024 / % possible all: 86.85

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Processing

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

4lvt


Resolution: 1.8→43.237 Å / SU ML: 0.3 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 27.55
RfactorNum. reflection% reflection
Rfree0.2319 672 4.97 %
Rwork0.1928 --
obs0.1949 13525 98.45 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.8→43.237 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1173 0 82 36 1291
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0031315
X-RAY DIFFRACTIONf_angle_d0.5651781
X-RAY DIFFRACTIONf_dihedral_angle_d18.382780
X-RAY DIFFRACTIONf_chiral_restr0.036172
X-RAY DIFFRACTIONf_plane_restr0.003262
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8-1.9390.42711210.33792362X-RAY DIFFRACTION92
1.939-2.13410.2761340.23252561X-RAY DIFFRACTION100
2.1341-2.44290.23231430.1912582X-RAY DIFFRACTION100
2.4429-3.07770.25541280.19082614X-RAY DIFFRACTION100
3.0777-43.24950.21460.17362734X-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)
13.7632-1.8535-3.34443.08982.4295.00920.1008-0.11240.276-0.0610.1089-0.21290.01410.2325-0.2520.24120.0037-0.03080.2267-0.01020.207-2.06676.6785-7.2494
24.99180.5997-0.52016.22934.5558.335-0.0742-0.1564-0.17230.38470.2294-0.36310.39920.2639-0.14910.23430.0188-0.03410.21650.03870.25162.7107-4.5625-7.89
35.43590.48520.96174.7631.67058.2605-0.06970.2069-0.6276-0.18360.1510.0340.15990.0626-0.18740.2972-0.03630.02660.2098-0.05530.3733-11.1869-4.1657-10.4859
43.9886-2.1779-2.85514.9362.47784.66310.25780.37440.1108-0.2886-0.19510.0237-0.0407-0.2287-0.08220.22830.0124-0.06390.2455-0.00070.2349-5.56575.1577-17.5144
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 164 through 203 )
2X-RAY DIFFRACTION2chain 'A' and (resid 9 through 90 )
3X-RAY DIFFRACTION3chain 'A' and (resid 91 through 118 )
4X-RAY DIFFRACTION4chain 'A' and (resid 119 through 163 )

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