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- PDB-4lxd: Bcl_2-Navitoclax Analog (without Thiophenyl) Complex -

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Basic information

Entry
Database: PDB / ID: 4lxd
TitleBcl_2-Navitoclax Analog (without Thiophenyl) Complex
ComponentsApoptosis regulator Bcl-2
KeywordsAPOPTOSIS REGULATOR/INHIBITOR / 8 helices / APOPTOSIS REGULATOR-INHIBITOR complex
Function / homology
Function and homology information


negative regulation of cellular pH reduction / negative regulation of retinal cell programmed cell death / pigment granule organization / channel inhibitor activity / CD8-positive, alpha-beta T cell lineage commitment / BAD-BCL-2 complex / regulation of glycoprotein biosynthetic process / melanin metabolic process / positive regulation of skeletal muscle fiber development / positive regulation of melanocyte differentiation ...negative regulation of cellular pH reduction / negative regulation of retinal cell programmed cell death / pigment granule organization / channel inhibitor activity / CD8-positive, alpha-beta T cell lineage commitment / BAD-BCL-2 complex / regulation of glycoprotein biosynthetic process / melanin metabolic process / positive regulation of skeletal muscle fiber development / positive regulation of melanocyte differentiation / myeloid cell apoptotic process / osteoblast proliferation / cochlear nucleus development / mesenchymal cell development / retinal cell programmed cell death / positive regulation of neuron maturation / negative regulation of osteoblast proliferation / gland morphogenesis / renal system process / regulation of cell-matrix adhesion / T cell apoptotic process / stem cell development / negative regulation of calcium ion transport into cytosol / The NLRP1 inflammasome / dendritic cell apoptotic process / melanocyte differentiation / ear development / lymphoid progenitor cell differentiation / negative regulation of myeloid cell apoptotic process / negative regulation of epithelial cell apoptotic process / regulation of nitrogen utilization / BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members / glomerulus development / B cell apoptotic process / negative regulation of T cell apoptotic process / negative regulation of dendritic cell apoptotic process / oocyte development / positive regulation of multicellular organism growth / neuron maturation / metanephros development / regulation of viral genome replication / negative regulation of motor neuron apoptotic process / focal adhesion assembly / endoplasmic reticulum calcium ion homeostasis / negative regulation of ossification / negative regulation of B cell apoptotic process / response to UV-B / response to iron ion / regulation of mitochondrial membrane permeability / calcium ion transport into cytosol / negative regulation of mitochondrial depolarization / motor neuron apoptotic process / channel activity / axon regeneration / epithelial cell apoptotic process / smooth muscle cell migration / intrinsic apoptotic signaling pathway in response to oxidative stress / NFE2L2 regulating tumorigenic genes / digestive tract morphogenesis / organ growth / branching involved in ureteric bud morphogenesis / cellular response to organic substance / hair follicle morphogenesis / negative regulation of G1/S transition of mitotic cell cycle / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / B cell lineage commitment / positive regulation of smooth muscle cell migration / B cell proliferation / pore complex / T cell homeostasis / BH3 domain binding / regulation of calcium ion transport / B cell homeostasis / humoral immune response / negative regulation of apoptotic signaling pathway / negative regulation of anoikis / extrinsic apoptotic signaling pathway via death domain receptors / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / Activation of BAD and translocation to mitochondria / hematopoietic stem cell differentiation / negative regulation of reactive oxygen species metabolic process / behavioral fear response / negative regulation of intrinsic apoptotic signaling pathway / cellular response to glucose starvation / skeletal muscle fiber development / homeostasis of number of cells within a tissue / positive regulation of B cell proliferation / ovarian follicle development / response to glucocorticoid / extrinsic apoptotic signaling pathway in absence of ligand / spleen development / reactive oxygen species metabolic process / ossification / axonogenesis / negative regulation of autophagy / post-embryonic development / negative regulation of cell migration / release of cytochrome c from mitochondria
Similarity search - Function
Apoptosis regulator, Bcl-2 / 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 / 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-1XV / Apoptosis regulator Bcl-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsPark, C.H.
CitationJournal: NAT.MED. (N.Y.) / Year: 2013
Title: ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets.
Authors: Souers, A.J. / Leverson, J.D. / Boghaert, E.R. / Ackler, S.L. / Catron, N.D. / Chen, J. / Dayton, B.D. / Ding, H. / Enschede, S.H. / Fairbrother, W.J. / Huang, D.C. / Hymowitz, S.G. / Jin, S. ...Authors: Souers, A.J. / Leverson, J.D. / Boghaert, E.R. / Ackler, S.L. / Catron, N.D. / Chen, J. / Dayton, B.D. / Ding, H. / Enschede, S.H. / Fairbrother, W.J. / Huang, D.C. / Hymowitz, S.G. / Jin, S. / Khaw, S.L. / Kovar, P.J. / Lam, L.T. / Lee, J. / Maecker, H.L. / Marsh, K.C. / Mason, K.D. / Mitten, M.J. / Nimmer, P.M. / Oleksijew, A. / Park, C.H. / Park, C.M. / Phillips, D.C. / Roberts, A.W. / Sampath, D. / Seymour, J.F. / Smith, M.L. / Sullivan, G.M. / Tahir, S.K. / Tse, C. / Wendt, M.D. / Xiao, Y. / Xue, J.C. / Zhang, H. / Humerickhouse, R.A. / Rosenberg, S.H. / Elmore, S.W.
History
DepositionJul 29, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 14, 2013Provider: repository / Type: Initial release
Revision 1.1Aug 2, 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: Apoptosis regulator Bcl-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,0802
Polymers19,3841
Non-polymers6961
Water4,161231
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)86.515, 86.515, 62.425
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number169
Space group name H-MP61

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Components

#1: Protein Apoptosis regulator Bcl-2


Mass: 19383.594 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 1-34, 92-207 / Mutation: A2P
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BCL2 / Production host: Escherichia coli (E. coli) / References: UniProt: P10415
#2: Chemical ChemComp-1XV / 4-(4-{[4-(4-chlorophenyl)-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide


Mass: 696.213 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H38ClN5O7S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 231 / Source method: isolated from a natural source / Formula: H2O

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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: 3.48 Å3/Da / Density % sol: 64.65 %
Crystal growTemperature: 296 K / Method: vapor diffusion / pH: 6.5
Details: 1.5 M (NH4)2SO4, 0.1 M MES, 8%(V/V) PEG400, pH 6.5, VAPOR DIFFUSION, temperature 296K

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Aug 6, 2007
RadiationMonochromator: mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→37.46 Å / Num. all: 21056 / Num. obs: 20997 / % possible obs: 99.72 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Biso Wilson estimate: 24.93 Å2
Reflection shellResolution: 1.9→1.99 Å / Num. unique all: 2705 / % possible all: 99.72

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
AMoREphasing
BUSTER2.11.2refinement
DENZOdata reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→37.46 Å / Cor.coef. Fo:Fc: 0.9434 / Cor.coef. Fo:Fc free: 0.9354 / SU R Cruickshank DPI: 0.106 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2124 1077 5.13 %RANDOM
Rwork0.18 ---
obs0.1816 20997 99.72 %-
all-21056 --
Displacement parametersBiso mean: 28.37 Å2
Baniso -1Baniso -2Baniso -3
1--1.2359 Å20 Å20 Å2
2---1.2359 Å20 Å2
3---2.4719 Å2
Refine analyzeLuzzati coordinate error obs: 0.185 Å
Refinement stepCycle: LAST / Resolution: 1.9→37.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1188 0 48 231 1467
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONo_bond_d0.011275HARMONIC2
X-RAY DIFFRACTIONo_angle_deg0.931726HARMONIC2
X-RAY DIFFRACTIONo_improper_angle_d2.97433SINUSOIDAL2
X-RAY DIFFRACTIONo_dihedral_angle_d18.230HARMONIC2
LS refinement shellResolution: 1.9→1.99 Å / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.2344 154 5.69 %
Rwork0.197 2551 -
all0.1991 2705 -
obs--99.72 %

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