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- PDB-6o0m: crystal structure of BCL-2 F104L mutation with venetoclax -

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Basic information

Entry
Database: PDB / ID: 6o0m
Titlecrystal structure of BCL-2 F104L 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 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 / 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: 1.75 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: Advisory / Data collection ...Advisory / Data collection / Database references / Derived calculations / Source and taxonomy / Structure summary
Category: entity / entity_name_com ...entity / entity_name_com / entity_src_gen / pdbx_validate_symm_contact / struct_conn / 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: Advisory / Derived calculations / Structure summary
Category: chem_comp / pdbx_validate_symm_contact / struct_conn
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)20,6166
Polymers19,3241
Non-polymers1,2935
Water1,54986
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)33.690, 48.270, 87.800
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: 19323.541 Da / Num. of mol.: 1 / Mutation: F104L,F104L,F104L
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 / 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: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 86 / 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: 1.85 Å3/Da / Density % sol: 33.41 %
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 17, 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: 1.75→43.9 Å / Num. obs: 15022 / % possible obs: 99.72 % / Redundancy: 5.8 % / CC1/2: 0.996 / Rrim(I) all: 0.1154 / Net I/σ(I): 10.58
Reflection shellResolution: 1.75→1.81 Å / Redundancy: 4.4 % / Mean I/σ(I) obs: 1.58 / Num. unique obs: 1427 / CC1/2: 0.436 / % possible all: 97.25

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Processing

Software
NameVersionClassification
PHENIX1.14_3260refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6O0G

6o0g


Resolution: 1.75→43.9 Å / SU ML: 0.23 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22
RfactorNum. reflection% reflection
Rfree0.2176 743 4.95 %
Rwork0.1725 --
obs0.1747 15011 99.72 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.75→43.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1164 0 89 86 1339
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0041475
X-RAY DIFFRACTIONf_angle_d0.7142009
X-RAY DIFFRACTIONf_dihedral_angle_d19.029898
X-RAY DIFFRACTIONf_chiral_restr0.04188
X-RAY DIFFRACTIONf_plane_restr0.004325
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7501-1.88520.30621420.25292771X-RAY DIFFRACTION99
1.8852-2.07490.24671420.17422812X-RAY DIFFRACTION100
2.0749-2.37510.18571530.15822815X-RAY DIFFRACTION100
2.3751-2.99230.21561470.16542863X-RAY DIFFRACTION100
2.9923-43.91370.2111590.16853007X-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)
12.229-0.5398-1.36551.93760.77352.17290.0361-0.13920.21420.04240.0457-0.18790.00380.1117-0.06960.13040.009-0.01650.1097-0.0230.1105-1.49577.0503-7.4584
23.58550.9510.52895.81762.48814.9175-0.0088-0.1715-0.1310.35280.031-0.11890.31860.06450.01430.12950.0067-0.00660.1050.00980.15272.8167-4.4824-8.3853
39.1962-0.7921.3283.072-0.22085.6952-0.0463-0.2401-0.39430.31110.0451-0.11010.32410.1238-0.21030.20550.01340.01420.13880.02080.1859-8.9229-4.8194-3.8582
48.3725-0.0511-2.77196.99875.18936.3188-0.33511.03120.0055-0.65250.26550.1932-0.3209-0.24640.08780.2813-0.0151-0.03950.2923-0.0370.2367-13.5727-3.3672-21.0642
52.5912-0.3854-0.83692.97570.33212.71160.15560.25590.1589-0.2809-0.0706-0.0868-0.0475-0.1369-0.0420.15010.0099-0.01420.08840.01120.125-5.27725.1678-17.719
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 164 through 203 )
2X-RAY DIFFRACTION2chain 'A' and (resid 8 through 90 )
3X-RAY DIFFRACTION3chain 'A' and (resid 91 through 107 )
4X-RAY DIFFRACTION4chain 'A' and (resid 108 through 118 )
5X-RAY DIFFRACTION5chain 'A' and (resid 119 through 163 )

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