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- PDB-4qvx: Discovery of a Potent and Selective BCL-XL Inhibitor That Demonst... -

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Basic information

Entry
Database: PDB / ID: 4qvx
TitleDiscovery of a Potent and Selective BCL-XL Inhibitor That Demonstrates Thrombocytopenia and Inhibits Tumor Growth in Vivo
ComponentsBcl-2-like protein 1
KeywordsAPOPTOSIS/INHIBITOR / 8 alpha helices / Anti-apoptotic / Pro-apoptotic / APOPTOSIS-INHIBITOR complex
Function / homology
Function and homology information


apoptotic process in bone marrow cell / SARS-CoV-1-mediated effects on programmed cell death / The NLRP1 inflammasome / 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 execution phase of apoptosis / negative regulation of dendritic cell apoptotic process ...apoptotic process in bone marrow cell / SARS-CoV-1-mediated effects on programmed cell death / The NLRP1 inflammasome / 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 execution phase of apoptosis / negative regulation of dendritic cell apoptotic process / 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 / cytoplasm / cytosol
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 / Blc2-like / Apoptosis Regulator Bcl-x ...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 / Blc2-like / Apoptosis Regulator Bcl-x / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-3CQ / Bcl-2-like protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsPark, C.H.
CitationJournal: ACS MED.CHEM.LETT. / Year: 2014
Title: Discovery of a Potent and Selective BCL-XL Inhibitor with in Vivo Activity.
Authors: Tao, Z.F. / Hasvold, L. / Wang, L. / Wang, X. / Petros, A.M. / Park, C.H. / Boghaert, E.R. / Catron, N.D. / Chen, J. / Colman, P.M. / Czabotar, P.E. / Deshayes, K. / Fairbrother, W.J. / ...Authors: Tao, Z.F. / Hasvold, L. / Wang, L. / Wang, X. / Petros, A.M. / Park, C.H. / Boghaert, E.R. / Catron, N.D. / Chen, J. / Colman, P.M. / Czabotar, P.E. / Deshayes, K. / Fairbrother, W.J. / Flygare, J.A. / Hymowitz, S.G. / Jin, S. / Judge, R.A. / Koehler, M.F. / Kovar, P.J. / Lessene, G. / Mitten, M.J. / Ndubaku, C.O. / Nimmer, P. / Purkey, H.E. / Oleksijew, A. / Phillips, D.C. / Sleebs, B.E. / Smith, B.J. / Smith, M.L. / Tahir, S.K. / Watson, K.G. / Xiao, Y. / Xue, J. / Zhang, H. / Zobel, K. / Rosenberg, S.H. / Tse, C. / Leverson, J.D. / Elmore, S.W. / Souers, A.J.
History
DepositionJul 16, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 22, 2015Provider: repository / Type: Initial release
Revision 1.1Jul 26, 2017Group: Refinement description / Source and taxonomy / Category: entity_src_gen / software
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)38,7194
Polymers37,3802
Non-polymers1,3402
Water2,756153
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Bcl-2-like protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,3602
Polymers18,6901
Non-polymers6701
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
B: Bcl-2-like protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,3602
Polymers18,6901
Non-polymers6701
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)73.107, 90.955, 83.736
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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 / Fragment: SEE REMARK 999
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-3CQ / 2-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-5-(3-{4-[3-(dimethylamino)prop-1-yn-1-yl]-2-fluorophenoxy}propyl)-1,3-thiazole-4-carboxylic acid


Mass: 669.788 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C35H32FN5O4S2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 153 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsPROTEIN CONSTRUCT COMPRISES UNP RESIDUES 1-23 AND 83-209 CONNECTED BY AN ASGGGGGGG LINKER.

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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: 1.86 Å3/Da / Density % sol: 33.94 %
Crystal growTemperature: 290 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 10.73 uM compound in DMSO + 2.14 uM protein in 25 mM Tris, 0.1 M sodium chloride, 10% v/v glycerol, 1 mM DTT, pH 8.0 incubated overnight at 277K then concentrated to 12 mg/mL, 1:1 protein ...Details: 10.73 uM compound in DMSO + 2.14 uM protein in 25 mM Tris, 0.1 M sodium chloride, 10% v/v glycerol, 1 mM DTT, pH 8.0 incubated overnight at 277K then concentrated to 12 mg/mL, 1:1 protein solution:reservoir solution (3 M sodium chloride, 0.1 M citric acid, pH 3.5) used in drop, VAPOR DIFFUSION, SITTING DROP, temperature 290K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Dec 16, 2010
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→56.98 Å / Num. all: 16611 / Num. obs: 16571 / % possible obs: 99.76 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Biso Wilson estimate: 31.257 Å2
Reflection shellResolution: 2.1→2.23 Å / % possible all: 99.76

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
MOLREPphasing
BUSTER-TNT2.5.1refinement
PROCESSdata reduction
PROCESSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→56.98 Å / Cross valid method: THROUGHOUT / σ(F): 1 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.257 837 5.05 %RANDOM
Rwork0.1911 ---
obs0.1942 16571 99.76 %-
all-16611 --
Displacement parametersBiso mean: 33.38 Å2
Baniso -1Baniso -2Baniso -3
1-4.75142448 Å20 Å20 Å2
2---1.53655263 Å20 Å2
3----3.21487185 Å2
Refinement stepCycle: LAST / Resolution: 2.1→56.98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2186 0 94 153 2433
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONo_angle_deg0.837
X-RAY DIFFRACTIONo_bond_d0.005
X-RAY DIFFRACTIONo_dihedral_angle_d20.107
LS refinement shellResolution: 2.1→2.23 Å / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.2529 120 4.58 %
Rwork0.2036 2499 -
all0.206 2619 -
obs--99.76 %

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