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- PDB-4c5d: Crystal structure of Bcl-xL in complex with benzoylurea compound (42) -

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Basic information

Entry
Database: PDB / ID: 4c5d
TitleCrystal structure of Bcl-xL in complex with benzoylurea compound (42)
ComponentsBCL-2-LIKE PROTEIN 1
KeywordsAPOPTOSIS / BCL-2
Function / homology
Function and homology information


dendritic cell apoptotic process / dendritic cell proliferation / apoptotic process in bone marrow cell / The NLRP1 inflammasome / positive regulation of mononuclear cell proliferation / SARS-CoV-1-mediated effects on programmed cell death / negative regulation of dendritic cell apoptotic process / 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 ...dendritic cell apoptotic process / dendritic cell proliferation / apoptotic process in bone marrow cell / The NLRP1 inflammasome / positive regulation of mononuclear cell proliferation / SARS-CoV-1-mediated effects on programmed cell death / negative regulation of dendritic cell apoptotic process / 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 mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / fertilization / regulation of growth / regulation of mitochondrial membrane permeability / apoptotic mitochondrial changes / germ cell development / Bcl-2 family protein complex / NFE2L2 regulating tumorigenic genes / hepatocyte apoptotic process / response to cycloheximide / STAT5 activation downstream of FLT3 ITD mutants / cellular response to alkaloid / negative regulation of release of cytochrome c from mitochondria / negative regulation of intrinsic apoptotic signaling pathway / negative regulation of reproductive process / negative regulation of developmental process / negative regulation of anoikis / ectopic germ cell programmed cell death / BH3 domain binding / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / epithelial cell proliferation / negative regulation of protein localization to plasma membrane / ovarian follicle development / negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / extrinsic apoptotic signaling pathway in absence of ligand / response to cytokine / release of cytochrome c from mitochondria / regulation of mitochondrial membrane potential / negative regulation of autophagy / cellular response to amino acid stimulus / regulation of cytokinesis / male gonad development / cellular response to gamma radiation / intrinsic apoptotic signaling pathway in response to DNA damage / endocytosis / RAS processing / in utero embryonic development / neuron apoptotic process / synaptic vesicle membrane / channel activity / nuclear membrane / Interleukin-4 and Interleukin-13 signaling / spermatogenesis / negative regulation of neuron apoptotic process / defense response to virus / mitochondrial outer membrane / mitochondrial inner membrane / positive regulation of apoptotic process / mitochondrial matrix / centrosome / negative regulation of apoptotic process / protein kinase binding / endoplasmic reticulum / 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-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-X0R / Bcl-2-like protein 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsRoy, M.J. / Brady, R.M. / Lessene, G. / Colman, P.M. / Czabotar, P.E.
CitationJournal: J.Med.Chem. / Year: 2014
Title: De-Novo Designed Library of Benzoylureas as Inhibitors of Bcl-Xl: Synthesis, Structural and Biochemical Characterization.
Authors: Brady, R.M. / Vom, A. / Roy, M.J. / Toovey, N. / Smith, B.J. / Moss, R.M. / Hazis, E. / Huang, D.C.S. / Parisot, J.P. / Yang, H. / Street, I.P. / Colman, P.M. / Czabotar, P.E. / Baell, J.B. / Lessene, G.
History
DepositionSep 11, 2013Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 5, 2014Provider: repository / Type: Initial release
Revision 1.1Mar 12, 2014Group: Database references
Revision 1.2Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / 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 / _pdbx_database_status.status_code_sf / _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)38,26420
Polymers35,8362
Non-polymers2,42818
Water1,820101
1
A: BCL-2-LIKE PROTEIN 1
B: BCL-2-LIKE PROTEIN 1
hetero molecules

A: BCL-2-LIKE PROTEIN 1
B: BCL-2-LIKE PROTEIN 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,52840
Polymers71,6724
Non-polymers4,85636
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation6_554-x,-x+y,-z-1/31
Buried area19350 Å2
ΔGint-210.9 kcal/mol
Surface area24530 Å2
MethodPISA
Unit cell
Length a, b, c (Å)64.138, 64.138, 132.376
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221
Components on special symmetry positions
IDModelComponents
11B-2045-

HOH

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Components

#1: Protein BCL-2-LIKE PROTEIN 1 / BCL2-L-1 / APOPTOSIS REGULATOR BCL-X


Mass: 17917.959 Da / Num. of mol.: 2 / Fragment: RESIDUES 1-26,83-209
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q07817
#2: Chemical ChemComp-X0R / (R)-3-(4-BROMOBENZYLTHIO)-2-(3-(3-((2,4-DIFLUOROPHENYL)ETHYNYL)BENZOYL)-3-PROPYLUREIDO)PROPANOIC ACID


Mass: 615.486 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H25BrF2N2O4S
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 101 / 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: 2.2 Å3/Da / Density % sol: 43.9 %
Description: LIGAND WAS REMOVED FROM STARTING MODEL FOR MOLECULAR REPLACEMENT. INITIAL REFINEMENT INCLUDED ONE ROUND OF SIMULATED ANNEALING.
Crystal growpH: 6.5
Details: 1.1 M (NH4)2SO4, 0.1 M MES PH 6.5, 25% (V/V) ETHYLENE GLYCOL

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX1 / Wavelength: 0.956591
DetectorType: ADSC QUANTUM 210r / Detector: CCD / Date: Mar 4, 2009 / Details: BEAMLINE OPTICS
RadiationMonochromator: BEAMLINE OPTICS / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.956591 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. obs: 14561 / % possible obs: 99.8 % / Observed criterion σ(I): 1.6 / Redundancy: 10.3 % / Biso Wilson estimate: 30.97 Å2 / Rmerge(I) obs: 0.25 / Net I/σ(I): 11.27
Reflection shellResolution: 2.3→2.44 Å / Redundancy: 7.88 % / Rmerge(I) obs: 1.39 / Mean I/σ(I) obs: 1.66 / % possible all: 98.9

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Processing

Software
NameVersionClassification
PHENIX(PHENIX.REFINE)refinement
XDSdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4C52

4c52


Resolution: 2.3→44.125 Å / SU ML: 0.27 / σ(F): 1.36 / Phase error: 23.33 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2416 752 5.2 %
Rwork0.1661 --
obs0.1699 14557 99.7 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 34.8 Å2
Refinement stepCycle: LAST / Resolution: 2.3→44.125 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2333 0 148 101 2582
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0112533
X-RAY DIFFRACTIONf_angle_d1.3063412
X-RAY DIFFRACTIONf_dihedral_angle_d16.619882
X-RAY DIFFRACTIONf_chiral_restr0.077340
X-RAY DIFFRACTIONf_plane_restr0.006433
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3002-2.47770.29371460.22912666X-RAY DIFFRACTION99
2.4777-2.72710.26561510.21522704X-RAY DIFFRACTION100
2.7271-3.12160.29791590.18172744X-RAY DIFFRACTION100
3.1216-3.93250.23311560.14362761X-RAY DIFFRACTION100
3.9325-44.13340.19431400.14452930X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 0.6892 Å / Origin y: -20.8476 Å / Origin z: -32.4325 Å
111213212223313233
T0.1503 Å2-0.0148 Å2-0.0201 Å2-0.1892 Å2-0.0141 Å2--0.2278 Å2
L0.721 °20.2364 °2-0.8664 °2-0.4601 °2-0.3972 °2--2.8094 °2
S-0.0332 Å °0.0347 Å °-0.068 Å °0.0036 Å °-0.0328 Å °-0.0212 Å °0.1329 Å °-0.141 Å °0.0688 Å °
Refinement TLS groupSelection details: ALL

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