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- PDB-6uvd: Crystal structure of BCL-XL bound to compound 2: (2R)-3-(Benzylsu... -

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Basic information

Entry
Database: PDB / ID: 6uvd
TitleCrystal structure of BCL-XL bound to compound 2: (2R)-3-(Benzylsulfanyl)-2-({[(4-methylphenyl)methyl] [(4 phenylphenyl)carbonyl] carbamoyl}amino) 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 / 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 / neuron apoptotic process / Interleukin-4 and Interleukin-13 signaling / defense response to virus / nuclear membrane / mitochondrial inner membrane / in utero embryonic development / negative regulation of neuron apoptotic process / 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-XOU / Bcl-2-like protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.15 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)37,88418
Polymers35,8362
Non-polymers2,04816
Water2,000111
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6120 Å2
ΔGint-48 kcal/mol
Surface area14960 Å2
MethodPISA
Unit cell
Length a, b, c (Å)97.149, 97.149, 74.235
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121

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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-XOU / (2R)-3-(Benzylsulfanyl)-2-({[(4-methylphenyl)methyl] [(4 phenylphenyl)carbonyl] carbamoyl}amino) propanoic acid


Mass: 538.657 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C32H30N2O4S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


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


Mass: 62.068 Da / Num. of mol.: 11 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 111 / 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: 2.82 Å3/Da / Density % sol: 56.41 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: 1.4 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: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: May 12, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.15→50 Å / Num. obs: 22376 / % possible obs: 99.6 % / Redundancy: 7.2 % / Biso Wilson estimate: 42.27 Å2 / Rmerge(I) obs: 0.07 / Χ2: 1.395 / Net I/σ(I): 16.8 / Num. measured all: 160447
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
2.15-2.237.10.54222051.4061100
2.23-2.327.20.41922351.3751100
2.32-2.427.20.32521911.3851100
2.42-2.557.20.24922421.3441100
2.55-2.717.20.19522111.41100
2.71-2.927.20.13422301.433199.8
2.92-3.217.20.09422341.408199.8
3.21-3.687.20.06422451.41199.8
3.68-4.637.20.04522471.422198.9
4.63-506.90.03223361.364198.3

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
BUSTER2.10.3refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2YXJ

2yxj


Resolution: 2.15→36.6 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.942 / SU ML: 0.24 / SU R Cruickshank DPI: 0.179 / Cross valid method: FREE R-VALUE / σ(F): 0 / SU R Blow DPI: 0.181 / SU Rfree Blow DPI: 0.157 / SU Rfree Cruickshank DPI: 0.157 / Phase error: 19.74
RfactorNum. reflection% reflectionSelection details
Rfree0.212 1095 4.91 %RANDOM
Rwork0.174 ---
obs0.176 22287 99.7 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 127.8 Å2 / Biso mean: 43.55 Å2 / Biso min: 25.03 Å2
Baniso -1Baniso -2Baniso -3
1-0.8316 Å20 Å20 Å2
2--0.8316 Å20 Å2
3----1.6632 Å2
Refine analyzeLuzzati coordinate error obs: 0.23 Å
Refinement stepCycle: final / Resolution: 2.15→36.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2285 0 137 111 2533
Biso mean--55.34 50.17 -
Num. residues----283
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d901SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes502HARMONIC5
X-RAY DIFFRACTIONt_it2605HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion296SEMIHARMONIC5
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_contact3271SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2605HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3509HARMONIC20.91
X-RAY DIFFRACTIONt_omega_torsion2.87
X-RAY DIFFRACTIONt_other_torsion17.08
LS refinement shellResolution: 2.15→2.16 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2636 32 7.17 %
Rwork0.1977 414 -
all0.2015 446 -
obs--100 %
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)
112.0021-0.7381.1570.638-0.004700.06290.18920.14160.0955-0.00450.0831-0.00120.0141-0.0584-0.0317-0.06040.0354-0.0630.0069-0.065230.8967-39.9876-15.1117
20.11350.1794-0.39460.574-0.93173.6320.00040.02820.16750.10670.0401-0.1571-0.13880.0451-0.0406-0.03210.0098-0.00370.05050.00540.034745.5629-38.3055-30.5814
30.63640.21950.13372.3138-0.0362.34550.05510.10150.054-0.31720.14790.14490.01810.0039-0.2029-0.0635-0.05270.03750.00950.0532-0.05339.4365-37.6943-47.8421
41.0079-0.15590.0946-0.516-0.7141.09080.04690.15810.0636-0.0158-0.017-0.0094-0.0128-0.0992-0.0299-0.0214-0.04290.010.06920.01820.01936.1336-36.5047-39.4825
5-0.07993.1219-0.58897.1907-0.659900.05540.0554-0.0812-0.17850.06420.07940.55680.0502-0.11970.1179-0.0125-0.00410.0003-0.03430.029843.0106-54.1936-39.4154
60.5927-1.2083.1552.91190.83670-0.0773-0.2184-0.31550.14910.1446-0.11570.4014-0.1093-0.0673-0.0010.0244-0.017-0.0648-0.0017-0.07448.1681-50.1217-28.773
70.565-0.54780.91120.20521.47732.8046-0.04030.0182-0.01280.4240.07920.19760.2178-0.0686-0.0389-0.0696-0.01740.02630.00960.0421-0.04533.8676-37.1921-29.0635
84.3423-2.45424.34840.3767-1.594410.33040.16850.16960.6250.0073-0.0253-0.1359-0.13280.0929-0.1431-0.0188-0.06640.0459-0.0555-0.00190.070538.8762-31.2638-11.2826
9-1.95150.34791.45645.14780.89224.08850.23-0.49450.1440.1094-0.0614-0.2450.0650.0531-0.1686-0.0305-0.03490.02170.0339-0.11260.037943.8856-35.52762.8156
10-1.477-0.52610.13876.2534-4.43051.9315-0.0019-0.1154-0.31520.12540.0954-0.15010.34360.142-0.09350.0655-0.0547-0.11330.0123-0.0460.12434.8144-53.16611.7095
114.22630.2534-0.33255.7464-0.00230.33950.2754-0.51690.03640.2114-0.10790.1330.14650.1009-0.16750.0126-0.14640.01910.0575-0.0141-0.093828.107-43.30173.8915
123.11481.3829-0.52480.561-0.00840.87340.1358-0.35280.02250.2822-0.0755-0.02610.0755-0.0176-0.0604-0.0585-0.0711-0.0043-0.0396-0.0046-0.083332.699-43.3486-4.1037
136.3739-2.0351-1.71126.0407-2.25068.35790.2722-0.0521.0796-0.2809-0.1847-0.2922-0.2836-0.1811-0.0875-0.08980.00430.0686-0.1292-0.02110.147225.7681-26.7098-8.1427
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|-3 - A|20 }A-3 - 20
2X-RAY DIFFRACTION2{ A|21 - A|111 }A21 - 111
3X-RAY DIFFRACTION3{ A|112 - A|136 }A112 - 136
4X-RAY DIFFRACTION4{ A|137 - A|177 }A137 - 177
5X-RAY DIFFRACTION5{ A|178 - A|186 }A178 - 186
6X-RAY DIFFRACTION6{ A|187 - A|197 }A187 - 197
7X-RAY DIFFRACTION7{ B|3 - B|83 }B3 - 83
8X-RAY DIFFRACTION8{ B|84 - B|100 }B84 - 100
9X-RAY DIFFRACTION9{ B|101 - B|111 }B101 - 111
10X-RAY DIFFRACTION10{ B|112 - B|119 }B112 - 119
11X-RAY DIFFRACTION11{ B|120 - B|130 }B120 - 130
12X-RAY DIFFRACTION12{ B|131 - B|177 }B131 - 177
13X-RAY DIFFRACTION13{ B|178 - B|196 }B178 - 196

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