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- PDB-4ieh: Crystal Structure of human Bcl-2 in complex with a small molecule... -

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Entry
Database: PDB / ID: 4ieh
TitleCrystal Structure of human Bcl-2 in complex with a small molecule inhibitor targeting Bcl-2 BH3 domain interactions
ComponentsApoptosis regulator Bcl-2, Bcl-2-like protein 1 chimera
KeywordsAPOPTOSIS/INHIBITOR / protein-protein interaction / alpha helical / pro-apoptosis / cytochrome c release / caspase activation / BIM / BAK / BAD / PUMA / APOPTOSIS-INHIBITOR complex
Function / homology
Function and homology information


negative regulation of cellular pH reduction / negative regulation of retinal cell programmed cell death / pigment granule organization / CD8-positive, alpha-beta T cell lineage commitment / BAD-BCL-2 complex / positive regulation of skeletal muscle fiber development / regulation of glycoprotein biosynthetic process / positive regulation of melanocyte differentiation / channel inhibitor activity / melanin metabolic process ...negative regulation of cellular pH reduction / negative regulation of retinal cell programmed cell death / pigment granule organization / CD8-positive, alpha-beta T cell lineage commitment / BAD-BCL-2 complex / positive regulation of skeletal muscle fiber development / regulation of glycoprotein biosynthetic process / positive regulation of melanocyte differentiation / channel inhibitor activity / melanin metabolic process / positive regulation of neuron maturation / myeloid cell apoptotic process / cochlear nucleus development / osteoblast proliferation / mesenchymal cell development / retinal cell programmed cell death / negative regulation of osteoblast proliferation / stem cell development / gland morphogenesis / apoptotic process in bone marrow cell / renal system process / regulation of cell-matrix adhesion / The NLRP1 inflammasome / dendritic cell apoptotic process / ear development / negative regulation of calcium ion transport into cytosol / dendritic cell proliferation / positive regulation of mononuclear cell proliferation / SARS-CoV-1-mediated effects on programmed cell death / 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 / regulation of nitrogen utilization / negative regulation of dendritic cell apoptotic process / glomerulus development / focal adhesion assembly / regulation of transmembrane transporter activity / negative regulation of T cell apoptotic process / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage / oocyte development / B cell apoptotic process / metanephros development / neuron maturation / negative regulation of motor neuron apoptotic process / Regulation of MITF-M-dependent genes involved in apoptosis / positive regulation of multicellular organism growth / regulation of viral genome replication / negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / endoplasmic reticulum calcium ion homeostasis / negative regulation of execution phase of apoptosis / regulation of mitochondrial membrane permeability / fertilization / regulation of growth / calcium ion transport into cytosol / response to UV-B / negative regulation of ossification / response to iron ion / epithelial cell apoptotic process / negative regulation of mitochondrial depolarization / Bcl-2 family protein complex / axon regeneration / motor neuron apoptotic process / positive regulation of smooth muscle cell migration / smooth muscle cell migration / NFE2L2 regulating tumorigenic genes / intrinsic apoptotic signaling pathway in response to oxidative stress / negative regulation of B cell apoptotic process / organ growth / hair follicle morphogenesis / branching involved in ureteric bud morphogenesis / response to cycloheximide / STAT5 activation downstream of FLT3 ITD mutants / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / B cell lineage commitment / hepatocyte apoptotic process / digestive tract morphogenesis / negative regulation of G1/S transition of mitotic cell cycle / cellular response to alkaloid / negative regulation of release of cytochrome c from mitochondria / pore complex / negative regulation of intrinsic apoptotic signaling pathway / negative regulation of reproductive process / negative regulation of developmental process / germ cell development / apoptotic mitochondrial changes / BH3 domain binding / T cell homeostasis / regulation of calcium ion transport / B cell homeostasis / humoral immune response / B cell proliferation / negative regulation of anoikis / negative regulation of apoptotic signaling pathway / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / extrinsic apoptotic signaling pathway via death domain receptors / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / Activation of BAD and translocation to mitochondria
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-2 family / BCL (B-Cell lymphoma); contains BH1, BH2 regions / Bcl2-like / Bcl-2, Bcl-2 homology region 1-3 / Apoptosis regulator proteins, Bcl-2 family / BCL2-like apoptosis inhibitors family profile. / Bcl-2-like superfamily
Similarity search - Domain/homology
Chem-1E9 / Apoptosis regulator Bcl-2 / Bcl-2-like protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsXie, X. / Kulathila, R.
CitationJournal: ACS Med Chem Lett / Year: 2013
Title: The role of the acidity of N-heteroaryl sulfonamides as inhibitors of bcl-2 family protein-protein interactions.
Authors: Toure, B.B. / Miller-Moslin, K. / Yusuff, N. / Perez, L. / Dore, M. / Joud, C. / Michael, W. / DiPietro, L. / van der Plas, S. / McEwan, M. / Lenoir, F. / Hoe, M. / Karki, R. / Springer, C. ...Authors: Toure, B.B. / Miller-Moslin, K. / Yusuff, N. / Perez, L. / Dore, M. / Joud, C. / Michael, W. / DiPietro, L. / van der Plas, S. / McEwan, M. / Lenoir, F. / Hoe, M. / Karki, R. / Springer, C. / Sullivan, J. / Levine, K. / Fiorilla, C. / Xie, X. / Kulathila, R. / Herlihy, K. / Porter, D. / Visser, M.
History
DepositionDec 13, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 10, 2013Provider: repository / Type: Initial release
Revision 1.1Sep 24, 2014Group: Database references
Revision 1.2Jul 26, 2017Group: Refinement description / Source and taxonomy / Category: entity_src_gen / software
Revision 1.3Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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 chimera
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,5142
Polymers19,6401
Non-polymers8741
Water3,315184
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)73.529, 73.529, 96.205
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212

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Components

#1: Protein Apoptosis regulator Bcl-2, Bcl-2-like protein 1 chimera / Bcl2-L-1 / Apoptosis regulator Bcl-X


Mass: 19639.832 Da / Num. of mol.: 1 / Fragment: SEE REMARK 999
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BCL2, BCL2L, BCL2L1, BCLX / Production host: Escherichia coli (E. coli) / References: UniProt: P10415, UniProt: Q07817
#2: Chemical ChemComp-1E9 / N-(6-{4-[(4'-chlorobiphenyl-2-yl)methyl]piperazin-1-yl}-1,1-dioxido-1,2-benzothiazol-3-yl)-4-{[(2R)-4-(dimethylamino)-1-(phenylsulfanyl)butan-2-yl]amino}-3-nitrobenzenesulfonamide


Mass: 874.490 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C42H44ClN7O6S3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 184 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsPROTEIN IS A CHIMERA COMPRISING RESIDUES 1-34 OF BCL-2 (UNP P10415), RESIDUES 29-44 OF BCL-X (UNP ...PROTEIN IS A CHIMERA COMPRISING RESIDUES 1-34 OF BCL-2 (UNP P10415), RESIDUES 29-44 OF BCL-X (UNP Q07817), AND RESIDUES 92-207 OF BCL-2 (UNP P10415).

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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: 3.31 Å3/Da / Density % sol: 62.84 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 8.6
Details: 0.05 M succinic acid, 0.25 M sodium malonate, 12% PEG3350, 0.1 M Tris-HCl, pH 8.6, VAPOR DIFFUSION, temperature 277.0K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 9, 2009
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→48.1 Å / Num. obs: 15960 / % possible obs: 99.8 % / Observed criterion σ(I): -3 / Redundancy: 7.1 % / Biso Wilson estimate: 32.1 Å2 / Rsym value: 0.094 / Net I/σ(I): 15.1
Reflection shellResolution: 2.1→2.15 Å / Redundancy: 7.1 % / Mean I/σ(I) obs: 3.9 / Num. unique all: 558 / Rsym value: 0.468 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHASESphasing
PHENIX(phenix.refine)refinement
XDSdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→45.74 Å / SU ML: 0.23 / Phase error: 19.49 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2183 798 5 %RANDOM
Rwork0.1787 ---
all0.1807 15959 --
obs0.1807 15959 99.79 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 46.182 Å2 / ksol: 0.321 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--3.7199 Å2-0 Å20 Å2
2---3.7199 Å2-0 Å2
3---7.4398 Å2
Refinement stepCycle: LAST / Resolution: 2.1→45.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1157 0 59 184 1400
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0061261
X-RAY DIFFRACTIONf_angle_d0.981713
X-RAY DIFFRACTIONf_dihedral_angle_d22.356442
X-RAY DIFFRACTIONf_chiral_restr0.061168
X-RAY DIFFRACTIONf_plane_restr0.006216
LS refinement shell

Refine-ID: X-RAY DIFFRACTION

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection obs% reflection obs (%)
2.1-2.23160.25281290.201824542454100
2.2316-2.40390.26381300.180324822482100
2.4039-2.64580.21131320.17524942494100
2.6458-3.02850.18931320.17425122512100
3.0285-3.81540.18761340.157925442544100
3.8154-45.75120.23181410.1842675267599

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