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- PDB-6vwc: Crystal structure of Bcl-xL in complex with tetrahydroisoquinolin... -

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Basic information

Entry
Database: PDB / ID: 6vwc
TitleCrystal structure of Bcl-xL in complex with tetrahydroisoquinoline-pyridine based inhibitors
ComponentsBcl-2-like protein 1
KeywordsAPOPTOSIS/APOPTOSIS INHIBITOR / Bcl-xL inhibitor / apoptosis / structure-based drug design / APOPTOSIS-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 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-RQ7 / Bcl-2-like protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.604 Å
AuthorsJudge, R.A. / Judd, A.S.
CitationJournal: Acs Med.Chem.Lett. / Year: 2020
Title: Discovery of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable BCL-X L Inhibitor.
Authors: Wang, L. / Doherty, G.A. / Judd, A.S. / Tao, Z.F. / Hansen, T.M. / Frey, R.R. / Song, X. / Bruncko, M. / Kunzer, A.R. / Wang, X. / Wendt, M.D. / Flygare, J.A. / Catron, N.D. / Judge, R.A. / ...Authors: Wang, L. / Doherty, G.A. / Judd, A.S. / Tao, Z.F. / Hansen, T.M. / Frey, R.R. / Song, X. / Bruncko, M. / Kunzer, A.R. / Wang, X. / Wendt, M.D. / Flygare, J.A. / Catron, N.D. / Judge, R.A. / Park, C.H. / Shekhar, S. / Phillips, D.C. / Nimmer, P. / Smith, M.L. / Tahir, S.K. / Xiao, Y. / Xue, J. / Zhang, H. / Le, P.N. / Mitten, M.J. / Boghaert, E.R. / Gao, W. / Kovar, P. / Choo, E.F. / Diaz, D. / Fairbrother, W.J. / Elmore, S.W. / Sampath, D. / Leverson, J.D. / Souers, A.J.
History
DepositionFeb 19, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 21, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 4, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Oct 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

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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)38,5554
Polymers37,3802
Non-polymers1,1752
Water5,513306
1
A: Bcl-2-like protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,2772
Polymers18,6901
Non-polymers5881
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Bcl-2-like protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,2772
Polymers18,6901
Non-polymers5881
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)33.304, 94.584, 54.272
Angle α, β, γ (deg.)90, 90.93, 90
Int Tables number4
Space group name H-MP1211

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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-RQ7 / 6-{8-[(1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}-3-{1-[(pyridin-4-yl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic acid


Mass: 587.651 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C32H25N7O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 306 / 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: 2.29 Å3/Da / Density % sol: 46.21 % / Description: Crystals grew as plates
Crystal growTemperature: 290 K / Method: vapor diffusion / pH: 8.5 / Details: 30%(w/v) PEG 10,000, 0.1M Tris Hcl pH 8.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Dec 9, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.604→47.29 Å / Num. obs: 41362 / % possible obs: 94.2 % / Redundancy: 3 % / Rmerge(I) obs: 0.049 / Net I/σ(I): 14.4
Reflection shellResolution: 1.604→1.61 Å / Rmerge(I) obs: 0.358 / Num. unique obs: 295

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4QVX

4qvx


Resolution: 1.604→47.29 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.932 / SU R Cruickshank DPI: 0.085 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.089 / SU Rfree Blow DPI: 0.084 / SU Rfree Cruickshank DPI: 0.082
RfactorNum. reflection% reflectionSelection details
Rfree0.2001 2074 -RANDOM
Rwork0.1787 ---
obs0.1798 41328 94.1 %-
Displacement parametersBiso mean: 21.43 Å2
Baniso -1Baniso -2Baniso -3
1-0.394 Å20 Å20.205 Å2
2---0.1094 Å20 Å2
3----0.2846 Å2
Refine analyzeLuzzati coordinate error obs: 0.2 Å
Refinement stepCycle: LAST / Resolution: 1.604→47.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2218 0 86 306 2610
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0082366HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.833203HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d805SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes486HARMONIC5
X-RAY DIFFRACTIONt_it2366HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion273SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact2550SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.35
X-RAY DIFFRACTIONt_other_torsion14.59
LS refinement shellResolution: 1.604→1.62 Å
RfactorNum. reflection% reflection
Rfree0.3365 42 -
Rwork0.2402 --
obs--68.41 %

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