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- PDB-4man: Bcl_2-Navitoclax Analog (with Indole) Complex -

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Basic information

Entry
Database: PDB / ID: 4man
TitleBcl_2-Navitoclax Analog (with Indole) 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 / melanocyte differentiation / The NLRP1 inflammasome / dendritic cell apoptotic process / 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 / B cell apoptotic process / negative regulation of T cell apoptotic process / glomerulus development / negative regulation of dendritic cell apoptotic process / oocyte development / positive regulation of multicellular organism growth / metanephros development / neuron maturation / 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 / regulation of mitochondrial membrane permeability / response to iron ion / calcium ion transport into cytosol / channel activity / negative regulation of mitochondrial depolarization / motor neuron apoptotic process / axon regeneration / epithelial cell apoptotic process / smooth muscle cell migration / intrinsic apoptotic signaling pathway in response to oxidative stress / NFE2L2 regulating tumorigenic genes / organ growth / digestive tract morphogenesis / branching involved in ureteric bud morphogenesis / 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 / pore complex / positive regulation of smooth muscle cell migration / B cell proliferation / T cell homeostasis / BH3 domain binding / regulation of calcium ion transport / B cell homeostasis / negative regulation of apoptotic signaling pathway / humoral immune response / 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 / cellular response to glucose starvation / skeletal muscle fiber development / negative regulation of intrinsic apoptotic signaling pathway / ovarian follicle development / positive regulation of B cell proliferation / response to glucocorticoid / homeostasis of number of cells within a tissue / extrinsic apoptotic signaling pathway in absence of ligand / spleen development / reactive oxygen species metabolic process / negative regulation of autophagy / negative regulation of cell migration / ossification / axonogenesis / release of cytochrome c from mitochondria / post-embryonic development
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-1Y1 / Apoptosis regulator Bcl-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.07 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
DepositionAug 16, 2013Deposition site: RCSB / Processing site: RCSB
SupersessionJan 29, 2014ID: 4LXE
Revision 1.0Jan 29, 2014Provider: repository / Type: Initial release
Revision 1.1Aug 2, 2017Group: Refinement description / Source and taxonomy / Category: entity_src_gen / software
Revision 1.2Nov 15, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.3Feb 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
B: Apoptosis regulator Bcl-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,5604
Polymers38,7152
Non-polymers1,8452
Water4,684260
1
A: Apoptosis regulator Bcl-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,2802
Polymers19,3581
Non-polymers9221
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Apoptosis regulator Bcl-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,2802
Polymers19,3581
Non-polymers9221
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)71.375, 71.375, 101.492
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number78
Space group name H-MP43

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Components

#1: Protein Apoptosis regulator Bcl-2


Mass: 19357.557 Da / Num. of mol.: 2 / Fragment: UNP RESIDUES 1-34, 92-207
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-1Y1 / 4-[4-({4'-chloro-3-[2-(dimethylamino)ethoxy]biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide


Mass: 922.487 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C48H52ClN7O8S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 260 / 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: 3.34 Å3/Da / Density % sol: 63.16 %
Crystal growTemperature: 296 K / Method: vapor diffusion / pH: 8.5
Details: 1.5 M Li2SO4, 0.1 M Tris HCl, pH 8.5, VAPOR DIFFUSION, temperature 296K

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 1 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Jun 13, 2008
RadiationMonochromator: Mirror / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.07→18.37 Å / Num. all: 30949 / Num. obs: 30912 / % possible obs: 99.88 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Biso Wilson estimate: 35.6 Å2
Reflection shellResolution: 2.07→2.14 Å / % possible all: 99.88

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Processing

Software
NameVersionClassification
MAR345CCD300data collection
AMoREphasing
BUSTER2.11.4refinement
DENZOdata reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.07→18.37 Å / Cor.coef. Fo:Fc: 0.926 / Cor.coef. Fo:Fc free: 0.9203 / SU R Cruickshank DPI: 0.16 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2336 1561 5.05 %RANDOM
Rwork0.2131 ---
obs0.2142 30912 99.88 %-
all-30949 --
Displacement parametersBiso mean: 38.18 Å2
Baniso -1Baniso -2Baniso -3
1--4.006 Å20 Å20 Å2
2---4.006 Å20 Å2
3---8.0121 Å2
Refine analyzeLuzzati coordinate error obs: 0.267 Å
Refinement stepCycle: LAST / Resolution: 2.07→18.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2266 0 130 260 2656
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012509HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.043425HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d840SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes58HARMONIC2
X-RAY DIFFRACTIONt_gen_planes416HARMONIC5
X-RAY DIFFRACTIONt_it2509HARMONIC20
X-RAY DIFFRACTIONt_omega_torsion2.63
X-RAY DIFFRACTIONt_other_torsion17.67
X-RAY DIFFRACTIONt_chiral_improper_torsion272SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact3055SEMIHARMONIC4
LS refinement shellResolution: 2.07→2.14 Å / Total num. of bins used: 16
RfactorNum. reflection% reflection
Rfree0.2351 157 5.55 %
Rwork0.2362 2672 -
all0.2362 2829 -
obs-2829 99.88 %

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