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- PDB-7lh7: Crystal structure of BCL-XL in complex with a benzothiazole-based... -

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Basic information

Entry
Database: PDB / ID: 7lh7
TitleCrystal structure of BCL-XL in complex with a benzothiazole-based inhibitor
ComponentsBcl-2-like protein 1
KeywordsAPOPTOSIS / Bcl-xL / structure-based drug design
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 mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage / negative regulation of dendritic cell apoptotic process ...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 mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / 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 / regulation of mitochondrial membrane permeability / fertilization / regulation of growth / Bcl-2 family protein complex / BH domain binding / NFE2L2 regulating tumorigenic genes / response to cycloheximide / negative regulation of release of cytochrome c from mitochondria / STAT5 activation downstream of FLT3 ITD mutants / cellular response to alkaloid / hepatocyte apoptotic process / negative regulation of reproductive process / negative regulation of developmental process / BH3 domain binding / germ cell development / apoptotic mitochondrial changes / negative regulation of anoikis / ectopic germ cell programmed cell death / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / 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 / extrinsic apoptotic signaling pathway in absence of ligand / ovarian follicle development / release of cytochrome c from mitochondria / negative regulation of autophagy / response to cytokine / epithelial cell proliferation / regulation of cytokinesis / regulation of mitochondrial membrane potential / cellular response to amino acid stimulus / cellular response to gamma radiation / synaptic vesicle membrane / intrinsic apoptotic signaling pathway in response to DNA damage / endocytosis / RAS processing / male gonad development / spermatogenesis / Interleukin-4 and Interleukin-13 signaling / defense response to virus / nuclear membrane / in utero embryonic development / neuron apoptotic process / 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 / BCL2-like apoptosis inhibitors family profile. / Apoptosis regulator proteins, Bcl-2 family / Bcl-2-like superfamily
Similarity search - Domain/homology
Chem-XZM / Bcl-2-like protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.409 Å
AuthorsJudge, R.A. / Tao, Z.
CitationJournal: ACS Medicinal Chemistry Letters / Year: 2021
Title: Structure-Based Design of A-1293102, a Potent and Selective BCL-XL Inhibitor
Authors: Tao, Z.F. / Wang, X. / Chen, J. / Ingram, J.P. / Jin, S. / Judge, R.A. / Kovar, P.J. / Park, C. / Sun, C. / Wakefield, B.D. / Zhou, L. / Zhang, H. / Elmore, S.W. / Phillips, D.C. / Judd, A.S. ...Authors: Tao, Z.F. / Wang, X. / Chen, J. / Ingram, J.P. / Jin, S. / Judge, R.A. / Kovar, P.J. / Park, C. / Sun, C. / Wakefield, B.D. / Zhou, L. / Zhang, H. / Elmore, S.W. / Phillips, D.C. / Judd, A.S. / Leverson, J.D. / Souers, A.J.
History
DepositionJan 21, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 23, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 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)39,3244
Polymers37,3802
Non-polymers1,9442
Water6,395355
1
A: Bcl-2-like protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,6622
Polymers18,6901
Non-polymers9721
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Bcl-2-like protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,6622
Polymers18,6901
Non-polymers9721
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)58.86, 88.91, 151.46
Angle α, β, γ (deg.)90, 90, 90
Int Tables number20
Space group name H-MC2221

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Components

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


Mass: 18689.816 Da / Num. of mol.: 2 / Mutation: W24A,E158K,D189A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BCL2L1, BCL2L, BCLX / Production host: Escherichia coli (E. coli) / References: UniProt: Q07817
#2: Chemical ChemComp-XZM / N-(1,3-benzothiazol-2-yl)-2-(4-{[(4-{[(2R)-4-(morpholin-4-yl)-1-(phenylsulfanyl)butan-2-yl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl)sulfonyl]carbamoyl}-1,3-thiazol-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxamide


Mass: 972.130 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C42H40F3N7O7S5 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 355 / 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: 2.65 Å3/Da / Density % sol: 53.6 %
Crystal growTemperature: 290 K / Method: counter-diffusion / pH: 4.2
Details: 20% (w/v) PEG 8000, 0.1 M phosphate-citrate pH 4.2, 0.2 M sodium chloride. The method was liquid-liquid counter diffusion

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.9765 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jan 15, 2011 / Details: Mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9765 Å / Relative weight: 1
ReflectionResolution: 1.409→46.69 Å / Num. obs: 76281 / % possible obs: 99.1 % / Redundancy: 7.1 % / CC1/2: 1 / Net I/σ(I): 17.8
Reflection shellResolution: 1.409→1.433 Å / Num. unique obs: 3793 / CC1/2: 0.789

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
XDSdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6VWC

6vwc


Resolution: 1.409→46.69 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.939 / SU R Cruickshank DPI: 0.054 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.057 / SU Rfree Blow DPI: 0.056 / SU Rfree Cruickshank DPI: 0.053
RfactorNum. reflection% reflectionSelection details
Rfree0.1986 3873 -RANDOM
Rwork0.1854 ---
obs0.186 76281 99.1 %-
Displacement parametersBiso mean: 23.69 Å2
Baniso -1Baniso -2Baniso -3
1--1.7304 Å20 Å20 Å2
2--3.5423 Å20 Å2
3----1.8119 Å2
Refine analyzeLuzzati coordinate error obs: 0.18 Å
Refinement stepCycle: LAST / Resolution: 1.409→46.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2293 0 128 355 2776
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0082485HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.863370HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d862SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes511HARMONIC5
X-RAY DIFFRACTIONt_it2485HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion282SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact2694SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.59
X-RAY DIFFRACTIONt_other_torsion13.69
LS refinement shellResolution: 1.41→1.42 Å
RfactorNum. reflection% reflection
Rfree0.2043 66 -
Rwork0.2073 --
obs0.2071 1526 99.79 %

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