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- PDB-6o0l: crystal structure of BCL-2 G101V mutation with venetoclax -

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Basic information

Entry
Database: PDB / ID: 6o0l
Titlecrystal structure of BCL-2 G101V 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 / resistance mutation / 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 iron ion / negative regulation of protein localization to plasma membrane / response to UV-B / negative regulation of mitochondrial depolarization / regulation of mitochondrial membrane permeability / regulation of growth / calcium ion transport into cytosol / channel activity / motor neuron apoptotic process / axon regeneration / Bcl-2 family protein complex / epithelial cell apoptotic process / 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 / branching involved in ureteric bud morphogenesis / cellular response to organic substance / 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 / hepatocyte apoptotic process / positive regulation of smooth muscle cell migration / B cell proliferation / pore complex / 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 / 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: 2.2 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 / 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
C: Apoptosis regulator Bcl-2,Bcl-2-like protein 1,Apoptosis regulator Bcl-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,03210
Polymers38,7992
Non-polymers2,2328
Water39622
1
A: Apoptosis regulator Bcl-2,Bcl-2-like protein 1,Apoptosis regulator Bcl-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,5165
Polymers19,4001
Non-polymers1,1164
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
C: Apoptosis regulator Bcl-2,Bcl-2-like protein 1,Apoptosis regulator Bcl-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,5165
Polymers19,4001
Non-polymers1,1164
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)33.147, 82.005, 47.508
Angle α, β, γ (deg.)90.00, 90.08, 90.00
Int Tables number4
Space group name H-MP1211

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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: 19399.637 Da / Num. of mol.: 2 / Mutation: G101V,G101V,G101V
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) / 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.: 2 / Source method: obtained synthetically / Formula: C45H50ClN7O7S / Feature type: SUBJECT OF INVESTIGATION / Comment: medication*YM
#3: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C4H10O3
#4: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 22 / 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: 1.66 Å3/Da / Density % sol: 26.09 %
Crystal growTemperature: 291 K / Method: vapor diffusion / Details: 4% PEG4K, 35% PEG400, 0.08M 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: Jul 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: 2.2→47.51 Å / Num. obs: 12909 / % possible obs: 99.84 % / Redundancy: 3.8 % / CC1/2: 0.991 / Rrim(I) all: 0.1432 / Net I/σ(I): 7.6
Reflection shellResolution: 2.2→2.28 Å / Redundancy: 3.7 % / Mean I/σ(I) obs: 1.56 / Num. unique obs: 1270 / CC1/2: 0.646 / % possible all: 99.53

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Processing

Software
NameVersionClassification
PHENIX(1.14_3260refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6O0G

6o0g


Resolution: 2.2→47.508 Å / SU ML: 0.25 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 27.34
Details: Authors state that the data were processed and refined in spacegroup P21, despite being possible to merge and refine in orthorhombic spacegroup P212121. This was due to poorer refinement ...Details: Authors state that the data were processed and refined in spacegroup P21, despite being possible to merge and refine in orthorhombic spacegroup P212121. This was due to poorer refinement statistics in the orthorhombic spacegroup.
RfactorNum. reflection% reflection
Rfree0.2268 628 4.86 %
Rwork0.1954 --
obs0.197 12924 99.84 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.2→47.508 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2328 0 152 22 2502
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0032550
X-RAY DIFFRACTIONf_angle_d0.5893449
X-RAY DIFFRACTIONf_dihedral_angle_d18.4661505
X-RAY DIFFRACTIONf_chiral_restr0.038334
X-RAY DIFFRACTIONf_plane_restr0.003505
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.42140.27871560.23533026X-RAY DIFFRACTION100
2.4214-2.77170.2921590.21823095X-RAY DIFFRACTION100
2.7717-3.49190.21541580.20593054X-RAY DIFFRACTION100
3.4919-47.5190.20411550.17623121X-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)
13.809-0.32610.74186.1047-0.51942.43320.17710.4439-0.2963-1.0320.2988-0.14790.06420.05860.0930.3344-0.0092-0.06560.34-0.0210.21339.24797.2737-5.3664
24.3852.2123.00253.6291-0.17224.7690.07950.8164-0.3613-0.35190.1691-0.09111.12460.0287-0.49660.6027-0.1655-0.09760.42060.08290.2157-2.6493.2669-5.088
38.29516.2242-5.35924.7725-4.1543.63440.5597-0.6487-0.10450.9529-0.234-0.0977-0.23280.1774-0.73160.6627-0.2248-0.24220.920.14630.558-7.303119.497-5.6781
43.49632.1552-1.25694.4856-1.80683.68840.0757-0.02480.26090.01210.04230.2914-0.21360.0058-0.10390.27520.0033-0.05140.21970.01170.16042.975713.60874.0071
53.31951.1681-1.27936.27831.92083.8076-0.03830.37940.296-0.86250.13710.07970.175-0.72810.05620.40710.0435-0.04720.4030.00150.28297.272837.044818.5847
66.6553-1.093-4.8844.73514.14877.573-0.22291.03570.7811-0.88550.3675-0.2476-0.96130.1756-0.80280.5095-0.16380.03730.42850.0380.309819.265340.883318.6098
70.5340.1186-0.33191.02360.68651.32040.0918-0.14890.1130.23470.0676-0.17010.380.21340.96810.82720.07360.12850.8687-0.3370.492823.951924.717917.9498
84.54992.72762.00882.80322.36796.34740.3670.2827-0.86060.80690.4779-0.77230.80370.225-0.59020.37310.0295-0.0920.2877-0.03960.397315.209422.543429.3811
94.62773.52222.73655.59272.12424.2495-0.01230.0182-0.0839-0.17770.1392-0.0272-0.1538-0.0022-0.15260.28050.00850.01830.26470.01320.167712.808933.940627.0697
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 107 )
3X-RAY DIFFRACTION3chain 'A' and (resid 108 through 117 )
4X-RAY DIFFRACTION4chain 'A' and (resid 118 through 203 )
5X-RAY DIFFRACTION5chain 'C' and (resid 8 through 90 )
6X-RAY DIFFRACTION6chain 'C' and (resid 91 through 107 )
7X-RAY DIFFRACTION7chain 'C' and (resid 108 through 117 )
8X-RAY DIFFRACTION8chain 'C' and (resid 118 through 143 )
9X-RAY DIFFRACTION9chain 'C' and (resid 144 through 203 )

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