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- PDB-6uvc: Crystal structure of BCL-XL bound to compound 8: (R)-3-(Benzylthi... -

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Basic information

Entry
Database: PDB / ID: 6uvc
TitleCrystal structure of BCL-XL bound to compound 8: (R)-3-(Benzylthio)-2-(3-(2-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-6-carbonyl)-3-(4-methylbenzyl)ureido)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 / dendritic cell apoptotic process / SARS-CoV-1-mediated effects on programmed cell death / 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 / dendritic cell apoptotic process / SARS-CoV-1-mediated effects on programmed cell death / 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 growth / regulation of mitochondrial membrane permeability / Bcl-2 family protein complex / BH domain binding / NFE2L2 regulating tumorigenic genes / response to cycloheximide / cellular response to alkaloid / STAT5 activation downstream of FLT3 ITD mutants / hepatocyte apoptotic process / negative regulation of release of cytochrome c from mitochondria / negative regulation of reproductive process / negative regulation of developmental process / 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 protein localization to plasma membrane / 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 cytokinesis / epithelial cell proliferation / response to cytokine / regulation of mitochondrial membrane potential / 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 / defense response to virus / neuron apoptotic process / in utero embryonic development / negative regulation of neuron apoptotic process / mitochondrial outer membrane / mitochondrial inner membrane / 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-XOY / Bcl-2-like protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.9 Å
AuthorsRoy, M.J. / Birkinshaw, R. / 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,11916
Polymers35,8362
Non-polymers2,28314
Water3,657203
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6370 Å2
ΔGint-39 kcal/mol
Surface area14570 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.437, 71.496, 111.324
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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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
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-XOY / (R)-3-(Benzylthio)-2-(3-(2-((4'-chloro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-6-carbonyl)-3-(4-methylbenzyl)ureido)propanoic acid


Mass: 718.303 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C42H40ClN3O4S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 203 / 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: 3.47 Å3/Da / Density % sol: 64.52 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 1.3 M ammonium sulphate, 0.1 M HEPES pH 6.5

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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 27, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. obs: 39075 / % possible obs: 97.4 % / Redundancy: 5.7 % / Biso Wilson estimate: 34.49 Å2 / Rmerge(I) obs: 0.06 / Χ2: 1.325 / Net I/σ(I): 17.5 / Num. measured all: 223691
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
1.9-1.975.10.8534501.397188
1.97-2.055.50.55336811.448193.2
2.05-2.145.60.35738531.461197.2
2.14-2.255.60.24338941.407198.5
2.25-2.395.60.16239531.384199
2.39-2.585.60.11539301.347199.3
2.58-2.845.80.07839951.252199.7
2.84-3.2560.05840301.1981100
3.25-4.096.20.04940581.4321100
4.09-506.10.02942311.013199.2

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
BUSTERrefinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2YXJ

2yxj


Resolution: 1.9→41.55 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.934 / SU ML: 0.22 / SU R Cruickshank DPI: 0.109 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / SU R Blow DPI: 0.113 / SU Rfree Blow DPI: 0.107 / SU Rfree Cruickshank DPI: 0.104 / Phase error: 22.3
RfactorNum. reflection% reflectionSelection details
Rfree0.207 1986 5.09 %RANDOM
Rwork0.183 ---
obs0.184 38991 97.5 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 139.38 Å2 / Biso mean: 44.76 Å2 / Biso min: 19.77 Å2
Baniso -1Baniso -2Baniso -3
1--1.0979 Å20 Å20 Å2
2---5.3104 Å20 Å2
3---6.4083 Å2
Refine analyzeLuzzati coordinate error obs: 0.22 Å
Refinement stepCycle: final / Resolution: 1.9→41.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2273 0 153 203 2629
Biso mean--58.58 52.29 -
Num. residues----282
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d894SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes519HARMONIC5
X-RAY DIFFRACTIONt_it2581HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion294SEMIHARMONIC5
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_contact3265SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2581HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3492HARMONIC20.89
X-RAY DIFFRACTIONt_omega_torsion2.53
X-RAY DIFFRACTIONt_other_torsion16.73
LS refinement shellResolution: 1.9→1.92 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.3264 56 7.18 %
Rwork0.263 724 -
all0.2672 780 -
obs--85.83 %
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)
14.4193-0.71652.19215.3122-0.64734.72510.04240.0821-0.0201-0.04890.11660.00720.0232-0.2322-0.1591-0.1063-0.033-0.03710.00610.1504-0.0923-5.7735-8.7071-20.0744
22.68281.2175-0.634.5078-3.272310.4603-0.006-0.05290.168-0.2145-0.02910.46610.0623-0.35450.0351-0.04370.0447-0.0210.0874-0.04180.0604-4.5485-21.3015-10.1864
30.65363.30535.762310.12262.74753.2204-0.0243-0.7861-0.08860.8608-0.0926-0.35220.024-0.63110.1168-0.07870.05830.00070.16580.0546-0.15431.6736-25.89187.7725
402.4558-2.021604.90315.27730.221-0.09020.0380.18750.2034-0.06490.4123-0.1124-0.4244-0.00660.0263-0.11220.1841-0.03620.002616.4459-20.57446.738
58.34460.75694.10813.46391.5237.92360.2378-0.4271-0.71210.37840.0059-0.36310.62520.3176-0.2437-0.00980.0822-0.0366-0.0260.0326-0.077311.3255-31.8618-2.0488
64.42640.19090.19623.88911.20072.8542-0.1066-0.27360.09080.32970.2158-0.24880.07050.3478-0.1092-0.02020.0603-0.03970.0852-0.0311-0.08019.9442-20.4749-3.9761
73.6456-1.5737-3.44123.92213.51916.20490.0020.3891-0.3677-0.305-0.16860.33440.0572-0.36240.1666-0.1034-0.0147-0.0148-0.091-0.0944-0.1525-0.3994-30.7238-17.6518
84.4281-0.5432-0.85445.06882.05474.1137-0.09610.10080.1712-0.0760.0628-0.045-0.1640.05740.0333-0.10.0233-0.04-0.03630.0103-0.10855.419-14.9183-10.139
910.4618-1.4014-0.19323.24170.05380.9080.02-0.56490.44930.41710.0726-0.211-0.1129-0.2736-0.09260.1455-0.0161-0.01090.22890.1292-0.0127-7.2879-3.461-10.0846
108.85723.4508-1.45735.0879-1.959210.62650.0277-0.05040.27970.2337-0.09980.3613-0.1413-0.57460.0721-0.25960.08870.07110.23680.2717-0.0152-24.3228-1.1351-16.9208
111.2101-2.0568-0.14680.87472.71232.3014-0.0645-0.09420.1877-0.6271-0.13150.1428-0.1452-0.49520.1960.144-0.0367-0.16330.55970.20860.293-20.9025-4.2431-33.2785
125.2603-1.4507-1.120710.62822.02077.566-0.04120.22480.2277-0.47950.54040.7126-1.043-0.9576-0.4993-0.21810.13190.0450.00780.2818-0.2064-15.71825.2327-28.692
134.621.72140.98635.3783-0.32843.5908-0.0288-0.25050.30970.1070.28360.3453-0.6665-0.7377-0.2549-0.11720.0840.04330.04980.191-0.1113-12.93482.0836-20.0501
144.80283.23320.353110.71682.0297.66350.09870.1789-0.0413-0.51490.21120.2504-0.0706-0.605-0.3099-0.02560.0203-0.01440.11330.1861-0.0193-8.9232-2.8866-29.1813
154.1015.78792.6524.11471.01730.0524-0.07950.02930.83690.83950.1908-0.6058-0.71010.3137-0.11130.2299-0.03940.0412-0.06750.02130.1077-0.25411.4559-16.9404
160-0.61722.35196.60991.10221.13760.0199-1.04820.74260.74110.0955-0.3801-0.58440.3173-0.1153-0.0338-0.0253-0.0231-0.0754-0.0105-0.2418-1.9294.3926-6.9553
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|2 - A|25 }A2 - 25
2X-RAY DIFFRACTION2{ A|26 - A|100 }A26 - 100
3X-RAY DIFFRACTION3{ A|101 - A|111 }A101 - 111
4X-RAY DIFFRACTION4{ A|112 - A|118 }A112 - 118
5X-RAY DIFFRACTION5{ A|119 - A|136 }A119 - 136
6X-RAY DIFFRACTION6{ A|137 - A|177 }A137 - 177
7X-RAY DIFFRACTION7{ A|178 - A|197 }A178 - 197
8X-RAY DIFFRACTION8{ B|0 - B|25 }B0 - 25
9X-RAY DIFFRACTION9{ B|26 - B|100 }B26 - 100
10X-RAY DIFFRACTION10{ B|101 - B|111 }B101 - 111
11X-RAY DIFFRACTION11{ B|112 - B|118 }B112 - 118
12X-RAY DIFFRACTION12{ B|119 - B|130 }B119 - 130
13X-RAY DIFFRACTION13{ B|131 - B|156 }B131 - 156
14X-RAY DIFFRACTION14{ B|157 - B|177 }B157 - 177
15X-RAY DIFFRACTION15{ B|178 - B|186 }B178 - 186
16X-RAY DIFFRACTION16{ B|187 - B|197 }B187 - 197

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