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- PDB-4ehr: Crystal structure of Bcl-Xl complex with 4-(5-butyl-3-(hydroxymet... -

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Basic information

Entry
Database: PDB / ID: 4ehr
TitleCrystal structure of Bcl-Xl complex with 4-(5-butyl-3-(hydroxymethyl)-1-phenyl-1h-pyrazol-4-yl)-3-(3,4-dihydro-2(1h)-isoquinolinylcarbonyl)-n-((2-(trimethylsilyl)ethyl)sulfonyl)benzamide
ComponentsBcl-2-like protein 1
KeywordsAPOPTOSIS / programmed cell death / bcl-2 family
Function / homology
Function and homology information


apoptotic process in bone marrow cell / The NLRP1 inflammasome / SARS-CoV-1-mediated effects on programmed cell death / 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 dendritic cell apoptotic process / negative regulation of execution phase of apoptosis ...apoptotic process in bone marrow cell / The NLRP1 inflammasome / SARS-CoV-1-mediated effects on programmed cell death / 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 dendritic cell apoptotic process / negative regulation of execution phase of apoptosis / negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / fertilization / negative regulation of protein localization to plasma membrane / regulation of mitochondrial membrane permeability / 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 / apoptotic mitochondrial changes / germ cell development / negative regulation of anoikis / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / ectopic germ cell programmed cell death / negative regulation of intrinsic apoptotic signaling pathway / negative regulation of endoplasmic reticulum stress-induced 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 / defense response to virus / neuron apoptotic process / Interleukin-4 and Interleukin-13 signaling / nuclear membrane / mitochondrial inner membrane / negative regulation of neuron apoptotic process / in utero embryonic development / mitochondrial outer membrane / mitochondrial matrix / protein heterodimerization activity / centrosome / negative regulation of apoptotic process / protein kinase binding / endoplasmic reticulum / protein homodimerization activity / mitochondrion / identical protein binding / cytosol / cytoplasm
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-0Q5 / IMIDAZOLE / Bcl-2-like protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.09 Å
AuthorsSchroeder, G.M. / Wei, D. / Banfi, P. / Cai, Z. / Lippy, J. / Menichincheri, M. / Modugno, M. / Naglich, J. / Penhallow, B. / Perez, H.L. ...Schroeder, G.M. / Wei, D. / Banfi, P. / Cai, Z. / Lippy, J. / Menichincheri, M. / Modugno, M. / Naglich, J. / Penhallow, B. / Perez, H.L. / Sack, J. / Schmidt, R.J. / Tebben, A. / Yan, C. / Zhang, L. / Galvani, A. / Lombardo, L.J. / Borzilleri, R.M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: Pyrazole and pyrimidine phenylacylsulfonamides as dual Bcl-2/Bcl-xL antagonists.
Authors: Schroeder, G.M. / Wei, D. / Banfi, P. / Cai, Z.W. / Lippy, J. / Menichincheri, M. / Modugno, M. / Naglich, J. / Penhallow, B. / Perez, H.L. / Sack, J. / Schmidt, R.J. / Tebben, A. / Yan, C. ...Authors: Schroeder, G.M. / Wei, D. / Banfi, P. / Cai, Z.W. / Lippy, J. / Menichincheri, M. / Modugno, M. / Naglich, J. / Penhallow, B. / Perez, H.L. / Sack, J. / Schmidt, R.J. / Tebben, A. / Yan, C. / Zhang, L. / Galvani, A. / Lombardo, L.J. / Borzilleri, R.M.
History
DepositionApr 3, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 6, 2012Provider: repository / Type: Initial release
Revision 1.1Jun 13, 2012Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / database_PDB_matrix / 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 / _database_PDB_matrix.origx[2][1] / _database_PDB_matrix.origx[2][2] / _database_PDB_matrix.origx[2][3] / _database_PDB_matrix.origx[3][1] / _database_PDB_matrix.origx[3][2] / _database_PDB_matrix.origx[3][3] / _database_PDB_matrix.origx_vector[2] / _database_PDB_matrix.origx_vector[3] / _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: Bcl-2-like protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,3373
Polymers19,5951
Non-polymers7422
Water61334
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)102.227, 102.227, 34.929
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number94
Space group name H-MP42212

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Components

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


Mass: 19595.492 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 1-209
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BCL2L1, BCL2L, BCLX / Plasmid: PET29B / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): HMS174 (DE3) / References: UniProt: Q07817
#2: Chemical ChemComp-0Q5 / 4-[5-butyl-3-(hydroxymethyl)-1-phenyl-1H-pyrazol-4-yl]-3-(3,4-dihydroisoquinolin-2(1H)-ylcarbonyl)-N-{[2-(trimethylsilyl)ethyl]sulfonyl}benzamide


Mass: 672.909 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C36H44N4O5SSi
#3: Chemical ChemComp-IMD / IMIDAZOLE / Imidazole


Mass: 69.085 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H5N2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 34 / 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: 2.33 Å3/Da / Density % sol: 47.18 %

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.98
DetectorType: RAYONIX MX-225 / Detector: CCD / Date: May 22, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.09→50 Å / Num. obs: 11425 / % possible obs: 99.4 % / Observed criterion σ(I): 0 / Redundancy: 12.5 % / Biso Wilson estimate: 39.94 Å2 / Rmerge(I) obs: 0.077 / Net I/σ(I): 25.8
Reflection shellResolution: 2.09→2.16 Å / Redundancy: 12.4 % / Rmerge(I) obs: 0.496 / Mean I/σ(I) obs: 6 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.2refinement
HKL-2000(DENZO)data reduction
HKL-2000(SCALEPACK)data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.09→45.72 Å / Cor.coef. Fo:Fc: 0.9375 / Cor.coef. Fo:Fc free: 0.9035 / SU R Cruickshank DPI: 0.205 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2827 582 5.15 %RANDOM
Rwork0.2329 ---
obs0.2354 11303 98.45 %-
Displacement parametersBiso mean: 45.8 Å2
Baniso -1Baniso -2Baniso -3
1-1.3175 Å20 Å20 Å2
2--1.3175 Å20 Å2
3----2.6351 Å2
Refine analyzeLuzzati coordinate error obs: 0.326 Å
Refinement stepCycle: LAST / Resolution: 2.09→45.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1085 0 52 34 1171
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.011168HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.141589HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d386SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes25HARMONIC2
X-RAY DIFFRACTIONt_gen_planes205HARMONIC5
X-RAY DIFFRACTIONt_it1168HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.27
X-RAY DIFFRACTIONt_other_torsion20.18
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion138SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact1430SEMIHARMONIC4
LS refinement shellResolution: 2.09→2.29 Å / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.3023 155 5.89 %
Rwork0.2768 2475 -
all0.2784 2630 -
obs--98.45 %

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