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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


Activation of BAD and translocation to mitochondria / BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members / Interleukin-4 and Interleukin-13 signaling / The NLRP1 inflammasome / Estrogen-dependent gene expression / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / CD8-positive, alpha-beta T cell lineage commitment / pigment granule organization / negative regulation of retinal cell programmed cell death / negative regulation of cellular pH reduction ...Activation of BAD and translocation to mitochondria / BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members / Interleukin-4 and Interleukin-13 signaling / The NLRP1 inflammasome / Estrogen-dependent gene expression / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / CD8-positive, alpha-beta T cell lineage commitment / pigment granule organization / negative regulation of retinal cell programmed cell death / negative regulation of cellular pH reduction / channel inhibitor activity / positive regulation of skeletal muscle fiber development / positive regulation of melanocyte differentiation / regulation of glycoprotein biosynthetic process / melanin metabolic process / cochlear nucleus development / negative regulation of osteoblast proliferation / mesenchymal cell development / glomerulus development / regulation of cell-matrix adhesion / oocyte development / negative regulation of calcium ion transport into cytosol / lymphoid progenitor cell differentiation / gland morphogenesis / renal system process / melanocyte differentiation / apoptotic process in bone marrow cell / ear development / channel activity / regulation of protein homodimerization activity / negative regulation of mitochondrial depolarization / positive regulation of neuron maturation / positive regulation of multicellular organism growth / negative regulation of ossification / cellular process regulating host cell cycle in response to virus / regulation of protein heterodimerization activity / negative regulation of myeloid cell apoptotic process / endoplasmic reticulum calcium ion homeostasis / metanephros development / negative regulation of protein localization to plasma membrane / B cell proliferation / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage / response to UV-B / organ growth / regulation of nitrogen utilization / fertilization / regulation of viral genome replication / negative regulation of execution phase of apoptosis / suppression by virus of host apoptotic process / focal adhesion assembly / intrinsic apoptotic signaling pathway in response to oxidative stress / BH3 domain binding / Bcl-2 family protein complex / mitochondrion morphogenesis / response to iron ion / response to cycloheximide / cellular response to alkaloid / B cell lineage commitment / negative regulation of G1/S transition of mitotic cell cycle / regulation of growth / digestive tract morphogenesis / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / axon regeneration / hair follicle morphogenesis / humoral immune response / apoptotic mitochondrial changes / branching involved in ureteric bud morphogenesis / positive regulation of smooth muscle cell migration / T cell homeostasis / behavioral fear response / pore complex / germ cell development / hepatocyte apoptotic process / negative regulation of apoptotic signaling pathway / negative regulation of release of cytochrome c from mitochondria / regulation of calcium ion transport / extrinsic apoptotic signaling pathway via death domain receptors / positive regulation of catalytic activity / regulation of mitochondrial membrane permeability / B cell homeostasis / cellular response to glucose starvation / regulation of transmembrane transporter activity / homeostasis of number of cells within a tissue / reactive oxygen species metabolic process / mitotic cell cycle checkpoint / negative regulation of reactive oxygen species metabolic process / negative regulation of anoikis / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / positive regulation of B cell proliferation / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / release of cytochrome c from mitochondria / negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / actin filament organization / ovarian follicle development / positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway / positive regulation of intrinsic apoptotic signaling pathway / negative regulation of cell migration / negative regulation of intrinsic apoptotic signaling pathway / cell aging / ossification
Apoptosis regulator, Bcl-2, BH1 motif, conserved site / Blc2-like superfamily / Apoptosis regulator proteins, Bcl-2 family / Blc2 family / Apoptosis regulator, Bcl-2, BH4 motif, conserved site / Apoptosis regulator, Bcl-2, BH3 motif, conserved site / Bcl-2 homology region 4 / Apoptosis regulator, Bcl-2 family BH1 motif signature. / Apoptosis regulator, Bcl-2 family BH2 motif signature. / Apoptosis regulator, Bcl-2 family BH3 motif signature. ...Apoptosis regulator, Bcl-2, BH1 motif, conserved site / Blc2-like superfamily / Apoptosis regulator proteins, Bcl-2 family / Blc2 family / Apoptosis regulator, Bcl-2, BH4 motif, conserved site / Apoptosis regulator, Bcl-2, BH3 motif, conserved site / Bcl-2 homology region 4 / Apoptosis regulator, Bcl-2 family BH1 motif signature. / Apoptosis regulator, Bcl-2 family BH2 motif signature. / Apoptosis regulator, Bcl-2 family BH3 motif signature. / Apoptosis regulator, Bcl-2 family BH4 motif signature. / BCL2-like apoptosis inhibitors family profile. / Apoptosis regulator, Bcl-2 family BH4 motif profile. / Bcl2-like / Apoptosis regulator, Bcl-2 protein, BH4 / Apoptosis regulator, Bcl-2/ BclX / Apoptosis regulator, Bcl-2 / Apoptosis regulator, Bcl-X / Apoptosis regulator, Bcl-2, BH2 motif, conserved site
Apoptosis regulator Bcl-2 / Bcl-2-like protein 1
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.
Validation Report
SummaryFull reportAbout validation report
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

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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)41,03410
Polymers38,7992
Non-polymers2,2348
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)20,5175
Polymers19,4001
Non-polymers1,1174
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)20,5175
Polymers19,4001
Non-polymers1,1174
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
γ
α
β
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/peptide 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-[[2-(4-chlorophenyl)-4,4-dimethyl-cyclohexen-1-yl]methyl]piperazin-1-yl]-~{N}-[4-(oxan-4-ylmethylamino)-3-[oxidanyl(oxidanylidene)-$l^{4}-azanyl]phenyl]sulfonyl-2-(1~{H}-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide / 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)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide


Mass: 869.447 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C45H51ClN7O7S
#3: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER


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


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


Mass: 18.015 Da / Num. of mol.: 22 / Source method: isolated from a natural source / Formula: H2O / Water

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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
PDB Unreleased entry


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 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

Refinement-ID: X-RAY DIFFRACTION

TypeDev idealNumber
f_bond_d0.0032550
f_angle_d0.5893449
f_dihedral_angle_d18.4661505
f_chiral_restr0.038334
f_plane_restr0.003505
LS refinement shell

Refinement-ID: X-RAY DIFFRACTION / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork
2.2-2.42140.27871560.23533026
2.4214-2.77170.2921590.21823095
2.7717-3.49190.21541580.20593054
3.4919-47.5190.20411550.17623121
Refinement TLS params.

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

IDL112)L122)L132)L222)L232)L332)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T112)T122)T132)T222)T232)T332)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

Refinement-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection details
11chain 'A' and (resid 9 through 90 )
22chain 'A' and (resid 91 through 107 )
33chain 'A' and (resid 108 through 117 )
44chain 'A' and (resid 118 through 203 )
55chain 'C' and (resid 8 through 90 )
66chain 'C' and (resid 91 through 107 )
77chain 'C' and (resid 108 through 117 )
88chain 'C' and (resid 118 through 143 )
99chain 'C' and (resid 144 through 203 )

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