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Yorodumi- PDB-6gl8: Crystal structure of Bcl-2 in complex with the novel orally activ... -
+Open data
-Basic information
Entry | Database: PDB / ID: 6gl8 | ||||||
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Title | Crystal structure of Bcl-2 in complex with the novel orally active inhibitor S55746 | ||||||
Components | Apoptosis regulator Bcl-2,Apoptosis regulator Bcl-2,Apoptosis regulator Bcl-2,Bcl-2-like protein 1,Apoptosis regulator Bcl-2,Apoptosis regulator Bcl-2,Apoptosis regulator Bcl-2 | ||||||
Keywords | APOPTOSIS / APOPTOSIS-INHIBITOR COMPLEX / BCL-2 / BH3-mimetics | ||||||
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 / positive regulation of skeletal muscle fiber development / melanin metabolic process / 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 / positive regulation of skeletal muscle fiber development / melanin metabolic process / positive regulation of melanocyte differentiation / myeloid cell apoptotic process / cochlear nucleus development / osteoblast proliferation / mesenchymal cell development / retinal cell programmed cell death / positive regulation of neuron maturation / negative regulation of osteoblast proliferation / gland morphogenesis / renal system process / regulation of cell-matrix adhesion / negative regulation of calcium ion transport into cytosol / stem cell development / The NLRP1 inflammasome / ear development / dendritic cell apoptotic process / lymphoid progenitor cell differentiation / melanocyte differentiation / T cell apoptotic process / negative regulation of myeloid cell apoptotic process / negative regulation of epithelial cell apoptotic process / BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members / B cell apoptotic process / negative regulation of T cell apoptotic process / negative regulation of dendritic cell apoptotic process / glomerulus development / regulation of nitrogen utilization / oocyte development / Regulation of MITF-M-dependent genes involved in apoptosis / neuron maturation / positive regulation of multicellular organism growth / metanephros development / negative regulation of motor neuron apoptotic process / focal adhesion assembly / regulation of viral genome replication / endoplasmic reticulum calcium ion homeostasis / negative regulation of ossification / negative regulation of B cell apoptotic process / regulation of mitochondrial membrane permeability / response to UV-B / response to iron ion / calcium ion transport into cytosol / negative regulation of mitochondrial depolarization / motor neuron apoptotic process / axon regeneration / epithelial cell apoptotic process / smooth muscle cell migration / BH domain binding / NFE2L2 regulating tumorigenic genes / intrinsic apoptotic signaling pathway in response to oxidative stress / organ growth / branching involved in ureteric bud morphogenesis / digestive tract 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 / B cell lineage commitment / positive regulation of smooth muscle cell migration / B cell proliferation / pore complex / T cell homeostasis / BH3 domain binding / B cell homeostasis / regulation of calcium ion transport / negative regulation of apoptotic signaling pathway / humoral immune response / negative regulation of anoikis / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / extrinsic apoptotic signaling pathway via death domain receptors / hematopoietic stem cell differentiation / Activation of BAD and translocation to mitochondria / negative regulation of reactive oxygen species metabolic process / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / behavioral fear response / negative regulation of intrinsic apoptotic signaling pathway / cellular response to glucose starvation / skeletal muscle fiber development / response to glucocorticoid / ovarian follicle development / positive regulation of B cell proliferation / extrinsic apoptotic signaling pathway in absence of ligand / spleen development / homeostasis of number of cells within a tissue / ossification / negative regulation of autophagy / reactive oxygen species metabolic process / axonogenesis / release of cytochrome c from mitochondria / post-embryonic development / thymus development Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.4 Å | ||||||
Authors | Casara, P. / Davidson, J. / Claperon, A. / Le Toumelin-Braizat, G. / Vogler, M. / Bruno, A. / Chanrion, M. / Lysiak-Auvity, G. / Le Diguarher, T. / Starck, J.B. ...Casara, P. / Davidson, J. / Claperon, A. / Le Toumelin-Braizat, G. / Vogler, M. / Bruno, A. / Chanrion, M. / Lysiak-Auvity, G. / Le Diguarher, T. / Starck, J.B. / Chen, I. / Whitehead, N. / Graham, C. / Matassova, N. / Dokurno, P. / Pedder, C. / Wang, Y. / Qiu, S. / Girard, A.M. / Schneider, E. / Grave, F. / Studeny, A. / Guasconi, G. / Rocchetti, F. / Maiga, S. / Henlin, J.M. / Colland, F. / Kraus-Berthier, L. / Le Gouill, S. / Dyer, M.J.S. / Hubbard, R. / Wood, M. / Amiot, M. / Cohen, G.M. / Hickman, J.A. / Morris, E. / Murray, J. / Geneste, O. | ||||||
Citation | Journal: Oncotarget / Year: 2018 Title: S55746 is a novel orally active BCL-2 selective and potent inhibitor that impairs hematological tumor growth. Authors: Casara, P. / Davidson, J. / Claperon, A. / Le Toumelin-Braizat, G. / Vogler, M. / Bruno, A. / Chanrion, M. / Lysiak-Auvity, G. / Le Diguarher, T. / Starck, J.B. / Chen, I. / Whitehead, N. / ...Authors: Casara, P. / Davidson, J. / Claperon, A. / Le Toumelin-Braizat, G. / Vogler, M. / Bruno, A. / Chanrion, M. / Lysiak-Auvity, G. / Le Diguarher, T. / Starck, J.B. / Chen, I. / Whitehead, N. / Graham, C. / Matassova, N. / Dokurno, P. / Pedder, C. / Wang, Y. / Qiu, S. / Girard, A.M. / Schneider, E. / Grave, F. / Studeny, A. / Guasconi, G. / Rocchetti, F. / Maiga, S. / Henlin, J.M. / Colland, F. / Kraus-Berthier, L. / Le Gouill, S. / Dyer, M.J.S. / Hubbard, R. / Wood, M. / Amiot, M. / Cohen, G.M. / Hickman, J.A. / Morris, E. / Murray, J. / Geneste, O. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 6gl8.cif.gz | 51.5 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6gl8.ent.gz | 34.8 KB | Display | PDB format |
PDBx/mmJSON format | 6gl8.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 6gl8_validation.pdf.gz | 872.3 KB | Display | wwPDB validaton report |
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Full document | 6gl8_full_validation.pdf.gz | 875.3 KB | Display | |
Data in XML | 6gl8_validation.xml.gz | 10.2 KB | Display | |
Data in CIF | 6gl8_validation.cif.gz | 14.1 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/gl/6gl8 ftp://data.pdbj.org/pub/pdb/validation_reports/gl/6gl8 | HTTPS FTP |
-Related structure data
Related structure data | 2w3lS S: Starting model for refinement |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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Unit cell |
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-Components
#1: Protein | Mass: 20236.555 Da / Num. of mol.: 1 Mutation: L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, ...Mutation: L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E,L95K, Q99E Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: BCL2, BCL2L1, BCL2L, BCLX / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): pLysS / References: UniProt: P10415 |
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#2: Chemical | ChemComp-F3Q / ~{ |
#3: Water | ChemComp-HOH / |
-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 1.76 Å3/Da / Density % sol: 29.7 % |
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Crystal grow | Temperature: 284 K / Method: vapor diffusion, hanging drop / pH: 5.25 Details: 0.1 M sodium acetate buffer pH 5.25, 20% Jeffamine600, 10% PEG3350 |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.97857 Å |
Detector | Type: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Nov 23, 2016 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.97857 Å / Relative weight: 1 |
Reflection | Resolution: 1.39→42.5 Å / Num. obs: 28969 / % possible obs: 98.9 % / Redundancy: 4.2 % / CC1/2: 0.999 / Rmerge(I) obs: 0.034 / Rpim(I) all: 0.019 / Rrim(I) all: 0.039 / Net I/σ(I): 19.5 |
Reflection shell | Resolution: 1.39→1.42 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.54 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 1967 / CC1/2: 0.877 / Rpim(I) all: 0.31 / Rrim(I) all: 0.63 / % possible all: 91.7 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 2W3L Resolution: 1.4→20 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.966 / SU B: 1.12 / SU ML: 0.044 / Cross valid method: THROUGHOUT / ESU R: 0.066 / ESU R Free: 0.064 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
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Solvent computation | Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 23.1 Å2
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Refinement step | Cycle: 1 / Resolution: 1.4→20 Å
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Refine LS restraints |
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