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- PDB-2w3l: Crystal Structure of Chimaeric Bcl2-xL and Phenyl Tetrahydroisoqu... -

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Basic information

Entry
Database: PDB / ID: 2w3l
TitleCrystal Structure of Chimaeric Bcl2-xL and Phenyl Tetrahydroisoquinoline Amide Complex
ComponentsAPOPTOSIS REGULATOR BCL-2
KeywordsAPOPTOSIS
Function / homology
Function and homology information


BCL-2 complex / BAD-BCL-2 complex / channel inhibitor activity / The NLRP1 inflammasome / BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members / hair follicle morphogenesis / regulation of viral genome replication / pigmentation / endoplasmic reticulum calcium ion homeostasis / Regulation of MITF-M-dependent genes involved in apoptosis ...BCL-2 complex / BAD-BCL-2 complex / channel inhibitor activity / The NLRP1 inflammasome / BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members / hair follicle morphogenesis / regulation of viral genome replication / pigmentation / endoplasmic reticulum calcium ion homeostasis / Regulation of MITF-M-dependent genes involved in apoptosis / regulation of mitochondrial membrane permeability / B cell proliferation / response to iron ion / negative regulation of mitochondrial depolarization / NFE2L2 regulating tumorigenic genes / pore complex / extrinsic apoptotic signaling pathway via death domain receptors / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / negative regulation of intrinsic apoptotic signaling pathway / humoral immune response / regulation of calcium ion transport / negative regulation of apoptotic signaling pathway / negative regulation of anoikis / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / extrinsic apoptotic signaling pathway in absence of ligand / BH3 domain binding / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of B cell proliferation / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / Activation of BAD and translocation to mitochondria / neuron apoptotic process / release of cytochrome c from mitochondria / response to cytokine / B cell receptor signaling pathway / regulation of mitochondrial membrane potential / negative regulation of autophagy / protein phosphatase 2A binding / response to nicotine / intrinsic apoptotic signaling pathway in response to DNA damage / female pregnancy / myelin sheath / response to radiation / response to toxic substance / protein polyubiquitination / positive regulation of cell growth / negative regulation of neuron apoptotic process / nuclear membrane / defense response to virus / channel activity / protease binding / Interleukin-4 and Interleukin-13 signaling / DNA-binding transcription factor binding / Estrogen-dependent gene expression / sequence-specific DNA binding / molecular adaptor activity / mitochondrial outer membrane / response to xenobiotic stimulus / positive regulation of apoptotic process / apoptotic process / protein heterodimerization activity / ubiquitin protein ligase binding / positive regulation of cell population proliferation / DNA damage response / negative regulation of apoptotic process / endoplasmic reticulum membrane / endoplasmic reticulum / protein-containing complex / mitochondrion / membrane / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Apoptosis regulator, Bcl-2 / 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 / Blc2-like / Apoptosis Regulator Bcl-x ...Apoptosis regulator, Bcl-2 / 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 / Blc2-like / Apoptosis Regulator Bcl-x / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-DRO / Apoptosis regulator Bcl-2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsPorter, J. / Payne, A. / de Candole, B. / Ford, D. / Hutchinson, B. / Trevitt, G. / Turner, J. / Edwards, C. / Watkins, C. / Whitcombe, I. ...Porter, J. / Payne, A. / de Candole, B. / Ford, D. / Hutchinson, B. / Trevitt, G. / Turner, J. / Edwards, C. / Watkins, C. / Whitcombe, I. / Davis, J. / Stubberfield, C. / Fisher, M. / Lamers, M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: Tetrahydroisoquinoline Amide Substituted Phenyl Pyrazoles as Selective Bcl-2 Inhibitors.
Authors: Porter, J. / Payne, A. / De Candole, B. / Ford, D. / Hutchinson, B. / Trevitt, G. / Turner, J. / Edwards, C. / Watkins, C. / Whitcombe, I. / Davis, J. / Stubberfield, C.
History
DepositionNov 13, 2008Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 9, 2008Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Jun 28, 2017Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.4May 8, 2024Group: Data collection / Database references / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: APOPTOSIS REGULATOR BCL-2
B: APOPTOSIS REGULATOR BCL-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9024
Polymers33,7502
Non-polymers1,1522
Water4,017223
1
A: APOPTOSIS REGULATOR BCL-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,4512
Polymers16,8751
Non-polymers5761
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
2
B: APOPTOSIS REGULATOR BCL-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,4512
Polymers16,8751
Non-polymers5761
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)68.000, 68.320, 70.670
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 / BCL2-XL


Mass: 16874.928 Da / Num. of mol.: 2 / Fragment: RESIDUES 9-33,92-206
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P10415
#2: Chemical ChemComp-DRO / 1-(2-{[(3S)-3-(aminomethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-4-chloro-5-methyl-N,N-diphenyl-1H-pyrazole-3-carboxamide


Mass: 576.087 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H30ClN5O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 223 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsTHE AUTHORS SUGGEST THE FLEXIBLE LOOP BETWEEN N- AND C-TERMINUS IS A CHIMERA

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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: 2.23 Å3/Da / Density % sol: 44.5 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54
DetectorType: RIGAKU (RAXIS4) / Detector: IMAGE PLATE / Date: Mar 13, 2006 / Details: VARIMAX-HF
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.1→19.91 Å / Num. obs: 22774 / % possible obs: 99.8 % / Observed criterion σ(I): 0.01 / Redundancy: 6.97 % / Rmerge(I) obs: 0.1 / Net I/σ(I): 8.4

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Processing

SoftwareName: REFMAC / Version: 5.2.0019 / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→20 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.921 / SU B: 5.425 / SU ML: 0.149 / Cross valid method: THROUGHOUT / ESU R: 0.261 / ESU R Free: 0.21 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.258 1012 5.1 %RANDOM
Rwork0.218 ---
obs0.218 18688 99.6 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 28.3 Å2
Baniso -1Baniso -2Baniso -3
1-2.91 Å20 Å20 Å2
2---1.96 Å20 Å2
3----0.95 Å2
Refinement stepCycle: LAST / Resolution: 2.1→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2318 0 84 223 2625
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0212476
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.7181.9513357
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3955279
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.18722.632133
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.50115370
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.9331523
X-RAY DIFFRACTIONr_chiral_restr0.1180.2327
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.021987
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2130.31204
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3160.51702
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2420.5263
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2040.368
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2570.530
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.2531.51435
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.97622224
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.09531234
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it4.7984.51133
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.1→2.15 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.303 71
Rwork0.235 1340

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