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- PDB-3wiz: Crystal structure of Bcl-xL in complex with compound 10 -

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Basic information

Entry
Database: PDB / ID: 3wiz
TitleCrystal structure of Bcl-xL in complex with compound 10
ComponentsBcl-2-like protein 1
KeywordsAPOPTOSIS / REGULATION
Function / homology
Function and homology information


apoptotic process in bone marrow cell / SARS-CoV-1-mediated effects on programmed cell death / The NLRP1 inflammasome / dendritic cell apoptotic process / dendritic cell proliferation / positive regulation of mononuclear cell proliferation / BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage / negative regulation of execution phase of apoptosis / negative regulation of dendritic cell apoptotic process ...apoptotic process in bone marrow cell / SARS-CoV-1-mediated effects on programmed cell death / The NLRP1 inflammasome / dendritic cell apoptotic process / dendritic cell proliferation / positive regulation of mononuclear cell proliferation / BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage / negative regulation of execution phase of apoptosis / negative regulation of dendritic cell apoptotic process / negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / fertilization / regulation of mitochondrial membrane permeability / negative regulation of protein localization to plasma membrane / regulation of growth / Bcl-2 family protein complex / NFE2L2 regulating tumorigenic genes / response to cycloheximide / cellular response to alkaloid / STAT5 activation downstream of FLT3 ITD mutants / hepatocyte apoptotic process / negative regulation of reproductive process / negative regulation of developmental process / negative regulation of release of cytochrome c from mitochondria / BH3 domain binding / germ cell development / apoptotic mitochondrial changes / negative regulation of anoikis / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / ectopic germ cell programmed cell death / negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / negative regulation of intrinsic apoptotic signaling pathway / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / ovarian follicle development / extrinsic apoptotic signaling pathway in absence of ligand / negative regulation of autophagy / release of cytochrome c from mitochondria / regulation of mitochondrial membrane potential / regulation of cytokinesis / epithelial cell proliferation / response to cytokine / cellular response to amino acid stimulus / cellular response to gamma radiation / synaptic vesicle membrane / endocytosis / RAS processing / male gonad development / intrinsic apoptotic signaling pathway in response to DNA damage / spermatogenesis / nuclear membrane / Interleukin-4 and Interleukin-13 signaling / neuron apoptotic process / defense response to virus / in utero embryonic development / mitochondrial outer membrane / negative regulation of neuron apoptotic process / mitochondrial inner membrane / mitochondrial matrix / protein heterodimerization activity / centrosome / negative regulation of apoptotic process / protein kinase binding / endoplasmic reticulum / protein homodimerization activity / mitochondrion / identical protein binding / cytoplasm / cytosol
Similarity search - Function
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-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-LC6 / PHOSPHATE ION / Bcl-2-like protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.45 Å
AuthorsSogabe, S. / Igaki, S. / Hayano, Y.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Discovery of potent Mcl-1/Bcl-xL dual inhibitors by using a hybridization strategy based on structural analysis of target proteins.
Authors: Tanaka, Y. / Aikawa, K. / Nishida, G. / Homma, M. / Sogabe, S. / Igaki, S. / Hayano, Y. / Sameshima, T. / Miyahisa, I. / Kawamoto, T. / Tawada, M. / Imai, Y. / Inazuka, M. / Cho, N. / Imaeda, Y. / Ishikawa, T.
History
DepositionSep 26, 2013Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 27, 2013Provider: repository / Type: Initial release
Revision 1.1Mar 12, 2014Group: Database references
Revision 1.2Aug 23, 2017Group: Refinement description / Source and taxonomy / Category: entity_src_gen / software
Revision 1.3Nov 8, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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

Downloads & links

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Assembly

Deposited unit
A: Bcl-2-like protein 1
B: Bcl-2-like protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,7336
Polymers40,7692
Non-polymers1,9644
Water30617
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7230 Å2
ΔGint-81 kcal/mol
Surface area15060 Å2
MethodPISA
Unit cell
Length a, b, c (Å)152.661, 152.661, 152.661
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number199
Space group name H-MI213
Components on special symmetry positions
IDModelComponents
11A-502-

PO4

21A-502-

PO4

31B-502-

PO4

41B-502-

PO4

51B-601-

HOH

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Components

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


Mass: 20384.369 Da / Num. of mol.: 2 / Fragment: UNP RESIDUES 1-44, 85-209
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BCL2L1, BCL2L, BCLX / Plasmid: pET21a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q07817
#2: Chemical ChemComp-LC6 / 7-(4-{[(4-{[(2R)-4-(dimethylamino)-1-(phenylsulfanyl)butan-2-yl]amino}-3-nitrophenyl)sulfonyl]carbamoyl}-2-methylphenyl)-3-[3-(naphthalen-1-yloxy)propyl]pyrazolo[1,5-a]pyridine-2-carboxylic acid


Mass: 887.034 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C47H46N6O8S2
#3: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 17 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsAMINO ACID NUMBERING BASED ON WILDTYPE HBCL-XL, GENEBANK ACCESSION CODE CAA80661

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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: 3.64 Å3/Da / Density % sol: 66.17 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.1M Na-K phosphate pH 6.5, 0.72M sodium malonate, 0.84% MEGA-8, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.976486 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Aug 31, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976486 Å / Relative weight: 1
ReflectionResolution: 2.45→50 Å / Num. obs: 21817 / % possible obs: 99.9 % / Redundancy: 5.5 % / Biso Wilson estimate: 54.3 Å2 / Rsym value: 0.072 / Net I/σ(I): 22.4
Reflection shellResolution: 2.45→2.49 Å / Redundancy: 5.6 % / Mean I/σ(I) obs: 2 / Rsym value: 0.892 / % possible all: 100

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Processing

Software
NameVersionClassification
MOLREPphasing
REFMAC5.7.0032refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2YXJ

2yxj


Resolution: 2.45→40 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.933 / SU B: 14.001 / SU ML: 0.145 / Cross valid method: THROUGHOUT / ESU R: 0.232 / ESU R Free: 0.205 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.23849 1112 5.1 %RANDOM
Rwork0.19562 ---
obs0.19774 20655 99.73 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 67.687 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 2.45→40 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2300 0 136 17 2453
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0192502
X-RAY DIFFRACTIONr_angle_refined_deg1.4551.9833396
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0025278
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.19824130
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.14815380
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.0141516
X-RAY DIFFRACTIONr_chiral_restr0.0880.2334
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.022138
X-RAY DIFFRACTIONr_mcbond_it8.8297.5751124
X-RAY DIFFRACTIONr_mcangle_it11.62912.711398
X-RAY DIFFRACTIONr_scbond_it13.8488.8011378
X-RAY DIFFRACTIONr_long_range_B_refined20.48236.8223945
LS refinement shellResolution: 2.452→2.516 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.295 86 -
Rwork0.285 1487 -
obs--99.87 %
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)
10.32480.00060.24270.259-0.26020.5731-0.04390.0383-0.0644-0.00360.0268-0.0002-0.05820.02020.01710.04150.00250.0070.0366-0.00510.053243.83247.8217-26.6658
20.19950.02660.2380.3583-0.20760.52970.041-0.00580.01440.0361-0.03790.06260.00180.0575-0.00310.0480.0040.00640.0465-0.00480.027445.97095.6551-11.4798
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A3 - 196
2X-RAY DIFFRACTION1A501
3X-RAY DIFFRACTION2B3 - 196
4X-RAY DIFFRACTION2B501

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