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- PDB-6o0o: crystal structure of BCL-2 G101V mutation with S55746 -

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Basic information

Entry
Database: PDB / ID: 6o0o
Titlecrystal structure of BCL-2 G101V mutation with S55746
ComponentsApoptosis regulator Bcl-2,Bcl-2-like protein 1,Apoptosis regulator Bcl-2
KeywordsAPOPTOSIS / BCL-2 / S55746 / complex / Protein-protein interface inhibitor / resistance mutation
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-F3Q / Apoptosis regulator Bcl-2 / Bcl-2-like protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.998 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 1.3Oct 11, 2023Group: 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
C: Apoptosis regulator Bcl-2,Bcl-2-like protein 1,Apoptosis regulator Bcl-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,2214
Polymers38,7992
Non-polymers1,4222
Water27015
1
A: Apoptosis regulator Bcl-2,Bcl-2-like protein 1,Apoptosis regulator Bcl-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,1102
Polymers19,4001
Non-polymers7111
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)20,1102
Polymers19,4001
Non-polymers7111
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)37.684, 68.584, 64.489
Angle α, β, γ (deg.)90.00, 96.67, 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 BL21 (bacteria) / Strain (production host): BL21 / References: UniProt: P10415, UniProt: Q07817
#2: Chemical ChemComp-F3Q / ~{N}-(4-hydroxyphenyl)-3-[6-[[(3~{S})-3-(morpholin-4-ylmethyl)-3,4-dihydro-1~{H}-isoquinolin-2-yl]carbonyl]-1,3-benzodioxol-5-yl]-~{N}-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamide


Mass: 710.817 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C43H42N4O6
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 15 / 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: 2.13 Å3/Da / Density % sol: 42.34 %
Crystal growTemperature: 291 K / Method: vapor diffusion / pH: 5 / Details: 0.1M NaCl 0.1M Succinic acid-NaOH pH5.0 10% PEG200

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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: Dec 14, 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: 1.998→37.43 Å / Num. obs: 22155 / % possible obs: 74.31 % / Redundancy: 6.7 % / CC1/2: 0.997 / Rrim(I) all: 0.148 / Net I/σ(I): 7.29
Reflection shellResolution: 2→2.07 Å / Redundancy: 6.6 % / Mean I/σ(I) obs: 0.9 / Num. unique obs: 468 / CC1/2: 0.596 / % possible all: 21.24

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Processing

Software
NameVersionClassification
PHENIX1.14_3260refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4LVT

4lvt


Resolution: 1.998→37.429 Å / SU ML: 0.3 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 42.25
Details: Authors state that the diffraction data were ellipsoidally truncated after 2.7 angstrom. Two copies of BCL-2 and S55746 are present in the assymetric unit. The model from chain A is the ...Details: Authors state that the diffraction data were ellipsoidally truncated after 2.7 angstrom. Two copies of BCL-2 and S55746 are present in the assymetric unit. The model from chain A is the preferred chain for analysis as the electron density for chain C is of poorer quality.
RfactorNum. reflection% reflection
Rfree0.2666 816 4.95 %
Rwork0.2167 --
obs0.2193 16500 74.32 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.998→37.429 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2288 0 106 15 2409
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0042471
X-RAY DIFFRACTIONf_angle_d0.5433353
X-RAY DIFFRACTIONf_dihedral_angle_d13.9991463
X-RAY DIFFRACTIONf_chiral_restr0.038327
X-RAY DIFFRACTIONf_plane_restr0.004507
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9981-2.12320.4024420.2936941X-RAY DIFFRACTION27
2.1232-2.28720.3655950.27931780X-RAY DIFFRACTION51
2.2872-2.51730.31891290.25912533X-RAY DIFFRACTION72
2.5173-2.88140.3551760.26493362X-RAY DIFFRACTION96
2.8814-3.62980.28781850.23493499X-RAY DIFFRACTION100
3.6298-37.43590.21931890.18243569X-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)
11.6656-0.17320.49711.8838-1.97283.205-0.0139-0.04140.28670.8516-0.06510.1352-0.7917-0.0163-0.08920.8213-0.1926-0.03820.33470.03760.296623.33495.898111.259
22.38410.6135-1.03290.8130.15181.36380.2917-0.26560.35020.23690.06270.1923-0.5173-0.1322.38630.77150.22880.25190.33710.04350.222910.90328.95836.4604
32.37110.29991.58412.2285-2.06833.45910.35790.1407-0.4840.1961-0.1102-0.65180.0527-0.0936-0.10010.58080.04970.18591.11470.25871.00424.2627-6.216510.8434
42.1707-1.31132.21993.7079-4.13675.7134-0.17610.24060.0525-0.80250.23620.48240.5223-0.1283-0.30590.5113-0.065-0.06880.32110.00920.226516.5565-10.33572.1359
51.0274-0.10730.19341.8776-1.75253.70520.1734-0.12180.13160.12290.02160.12570.03460.0383-0.09210.3202-0.03650.02110.21720.03210.1319.45650.80112.3879
60.18250.08580.32910.7013-0.38741.0148-0.1227-0.4099-0.2551-0.07010.1718-0.36150.35720.51210.68390.02660.11080.04230.2195-0.07220.402427.0846-36.733321.0507
73.5734-3.3748-1.535.97270.34542.3975-0.3656-0.3686-0.56890.70560.13560.3357-0.4435-0.1811-0.04490.42080.0245-0.21760.27050.06660.520923.9635-39.977634.1526
81.39540.14060.2521.6081-1.81032.21930.52510.3109-0.27610.47360.43180.23520.0270.0669-0.24691.13850.1430.06730.86520.10970.566716.7083-24.905536.1925
90.7267-0.33130.90410.9648-1.31612.1473-0.103-0.17290.13251.0880.1804-0.3758-0.533-0.11640.27960.45870.0721-0.21280.3443-0.01170.353229.0207-24.661431.394
100.6995-0.79951.24151.3507-1.46252.19170.1640.3347-0.159-0.0848-0.2488-0.47280.39960.54120.08360.2240.0733-0.10130.2965-0.03330.405535.0954-33.148329.7811
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 9 through 50 )
2X-RAY DIFFRACTION2chain 'A' and (resid 51 through 66 )
3X-RAY DIFFRACTION3chain 'A' and (resid 67 through 77 )
4X-RAY DIFFRACTION4chain 'A' and (resid 78 through 102 )
5X-RAY DIFFRACTION5chain 'A' and (resid 103 through 162 )
6X-RAY DIFFRACTION6chain 'C' and (resid 10 through 50 )
7X-RAY DIFFRACTION7chain 'C' and (resid 51 through 66 )
8X-RAY DIFFRACTION8chain 'C' and (resid 67 through 77 )
9X-RAY DIFFRACTION9chain 'C' and (resid 78 through 122 )
10X-RAY DIFFRACTION10chain 'C' and (resid 123 through 162 )

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