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- PDB-6uvh: Crystal structure of BCL-XL bound to compound 15: (R)-2-(3-(2-((4... -

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Basic information

Entry
Database: PDB / ID: 6uvh
TitleCrystal structure of BCL-XL bound to compound 15: (R)-2-(3-(2-((4'-Chloro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-6-carbonyl)-3-(4-methylbenzyl)ureido)-3-((cyclohexylmethyl)sulfonyl)propanoic acid
ComponentsBcl-2-like protein 1
KeywordsApoptosis/INHIBITOR / Apoptosis / BCL-2 family / BCL-XL / inhibitor / Apoptosis-INHIBITOR complex
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 / 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 / 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-QHJ / Bcl-2-like protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.19 Å
AuthorsRoy, M.J. / Lessene, G. / Czabotar, P.E.
Funding support Australia, 1items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia) Australia
CitationJournal: J.Med.Chem. / Year: 2021
Title: Structure-Guided Development of Potent Benzoylurea Inhibitors of BCL-X L and BCL-2.
Authors: Roy, M.J. / Vom, A. / Okamoto, T. / Smith, B.J. / Birkinshaw, R.W. / Yang, H. / Abdo, H. / White, C.A. / Segal, D. / Huang, D.C.S. / Baell, J.B. / Colman, P.M. / Czabotar, P.E. / Lessene, G.
History
DepositionNov 2, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 5, 2021Provider: repository / Type: Initial release
Revision 1.1May 12, 2021Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2May 26, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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
C: Bcl-2-like protein 1
D: Bcl-2-like protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)74,95111
Polymers71,6724
Non-polymers3,2807
Water1,72996
1
A: Bcl-2-like protein 1
B: Bcl-2-like protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,5076
Polymers35,8362
Non-polymers1,6714
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4180 Å2
ΔGint-28 kcal/mol
Surface area14160 Å2
MethodPISA
2
C: Bcl-2-like protein 1
D: Bcl-2-like protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,4455
Polymers35,8362
Non-polymers1,6093
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4570 Å2
ΔGint-49 kcal/mol
Surface area14510 Å2
MethodPISA
Unit cell
Length a, b, c (Å)152.026, 65.931, 77.133
Angle α, β, γ (deg.)90.000, 98.710, 90.000
Int Tables number5
Space group name H-MC121

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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.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BCL2L1, BCL2L, BCLX / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q07817
#2: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-QHJ / (R)-2-(3-(2-((4'-Chloro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-6-carbonyl)-3-(4-methylbenzyl)ureido)-3-((cyclohexylmethyl)sulfonyl)propanoic acid


Mass: 756.349 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C42H46ClN3O6S / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 96 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.67 Å3/Da / Density % sol: 53.86 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 1.3 M ammonium sulfate, 0.1 M Tris pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.9537 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Oct 17, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 2.19→30.26 Å / Num. obs: 38181 / % possible obs: 97.8 % / Redundancy: 3.768 % / Biso Wilson estimate: 46.88 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.074 / Rrim(I) all: 0.086 / Χ2: 0.971 / Net I/σ(I): 11.66 / Num. measured all: 143865
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
2.19-2.323.7310.7941.7821531624357710.6940.92692.4
2.32-2.483.8420.5172.7822228586857860.840.698.6
2.48-2.683.8410.3244.3320955553854550.9230.37798.5
2.68-2.943.8240.1797.419088504849920.9740.20898.9
2.94-3.283.8080.10212.1417367460845610.990.11999
3.28-3.793.7560.05520.315075406040140.9960.06498.9
3.79-4.643.6760.04227.0712562344634170.9970.04999.2
4.64-6.553.6040.03929.259587268326600.9970.04599.1
6.55-30.263.5880.03133.565472154215250.9980.03698.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
XSCALEdata scaling
PHASERphasing
BUSTERrefinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2YXJ

2yxj


Resolution: 2.19→30.26 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.93 / SU R Cruickshank DPI: 0.231 / Cross valid method: FREE R-VALUE / σ(F): 0 / SU R Blow DPI: 0.221 / SU Rfree Blow DPI: 0.18 / SU Rfree Cruickshank DPI: 0.186
RfactorNum. reflection% reflectionSelection details
Rfree0.237 1908 5 %RANDOM
Rwork0.207 ---
obs0.208 38168 97.8 %-
Displacement parametersBiso max: 156.51 Å2 / Biso mean: 62.34 Å2 / Biso min: 21.6 Å2
Baniso -1Baniso -2Baniso -3
1-4.2796 Å20 Å21.8732 Å2
2---10.5513 Å20 Å2
3---6.2717 Å2
Refine analyzeLuzzati coordinate error obs: 0.33 Å
Refinement stepCycle: final / Resolution: 2.19→30.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4501 0 226 96 4823
Biso mean--74.96 50.41 -
Num. residues----561
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1678SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes954HARMONIC5
X-RAY DIFFRACTIONt_it4868HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion564SEMIHARMONIC5
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_contact5745SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4868HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6615HARMONIC20.96
X-RAY DIFFRACTIONt_omega_torsion2.52
X-RAY DIFFRACTIONt_other_torsion18.78
LS refinement shellResolution: 2.19→2.21 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2551 38 4.97 %
Rwork0.2516 726 -
all0.2518 764 -
obs--66.46 %
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)
11.327-0.187-0.24873.45722.24232.0383-0.03460.15420.1006-0.62490.2028-0.2008-0.3265-0.0746-0.1682-0.0352-0.0999-0.0093-0.0560.0308-0.166541.5788-9.736119.8652
22.8867-3.1534-2.75214.15824.2488.07760.18970.39350.11770.12170.0219-0.45710.28890.6919-0.2116-0.2403-0.15840.0049-0.0093-0.0607-0.299150.52-28.22825.0371
31.991.9151-0.06781.6020.18511.309-0.11140.14270.33850.02880.06110.4804-0.1882-0.20450.0503-0.138-0.0274-0.0128-0.010.0272-0.000314.2063-26.75528.1011
45.6959-0.08880.06172.15821.05482.05230.09250.8169-0.69250.2139-0.18380.1580.3572-0.22280.0913-0.2327-0.1150.02750.0372-0.0984-0.13081.6036-48.101821.4918
50.96120.2651-0.64920.58980.5060.9712-0.02180.11620.0022-0.0311-0.03730.1804-0.0403-0.01890.0591-0.00730.0548-0.1399-0.01470.0896-0.100232.2392-27.287616.4739
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|-1 - A|196 }A-1 - 196
2X-RAY DIFFRACTION2{ B|1 - B|196 }B1 - 196
3X-RAY DIFFRACTION3{ C|1 - C|196 }C1 - 196
4X-RAY DIFFRACTION4{ D|1 - D|196 }D1 - 196
5X-RAY DIFFRACTION5{ A|303 - A|303 C|301 - C|301 B|301 - B|301 D|302 - D|302 }A303
6X-RAY DIFFRACTION5{ A|303 - A|303 C|301 - C|301 B|301 - B|301 D|302 - D|302 }C301
7X-RAY DIFFRACTION5{ A|303 - A|303 C|301 - C|301 B|301 - B|301 D|302 - D|302 }B301
8X-RAY DIFFRACTION5{ A|303 - A|303 C|301 - C|301 B|301 - B|301 D|302 - D|302 }D302

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