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- PDB-8vxm: Human Bcl-2/Bcl-xL Chimera Fused to MBP in Complex with Inhibitor... -

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Basic information

Entry
Database: PDB / ID: 8vxm
TitleHuman Bcl-2/Bcl-xL Chimera Fused to MBP in Complex with Inhibitor S55746
ComponentsMaltose/maltodextrin-binding periplasmic protein fused to apoptosis regulator Bcl-2/Bcl-xL chimera
KeywordsAPOPTOSIS / Bcl-2 / MBP Fusion / Bcl-xL Chimera / S55746 / Complex / Protein-Protein Interface Inhibitor
Function / homology
Function and homology information


negative regulation of cellular pH reduction / negative regulation of retinal cell programmed cell death / pigment granule organization / CD8-positive, alpha-beta T cell lineage commitment / BAD-BCL-2 complex / positive regulation of skeletal muscle fiber development / regulation of glycoprotein biosynthetic process / positive regulation of melanocyte differentiation / channel inhibitor activity / melanin metabolic process ...negative regulation of cellular pH reduction / negative regulation of retinal cell programmed cell death / pigment granule organization / CD8-positive, alpha-beta T cell lineage commitment / BAD-BCL-2 complex / positive regulation of skeletal muscle fiber development / regulation of glycoprotein biosynthetic process / positive regulation of melanocyte differentiation / channel inhibitor activity / melanin metabolic process / positive regulation of neuron maturation / myeloid cell apoptotic process / cochlear nucleus development / osteoblast proliferation / mesenchymal cell development / retinal cell programmed cell death / negative regulation of osteoblast proliferation / stem cell development / gland morphogenesis / apoptotic process in bone marrow cell / renal system process / regulation of cell-matrix adhesion / The NLRP1 inflammasome / dendritic cell apoptotic process / ear development / negative regulation of calcium ion transport into cytosol / dendritic cell proliferation / SARS-CoV-1-mediated effects on programmed cell death / positive regulation of mononuclear cell proliferation / lymphoid progenitor cell differentiation / T cell apoptotic process / melanocyte differentiation / negative regulation of myeloid cell apoptotic process / negative regulation of epithelial cell apoptotic process / BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members / regulation of nitrogen utilization / negative regulation of dendritic cell apoptotic process / glomerulus development / focal adhesion assembly / regulation of transmembrane transporter activity / negative regulation of T cell apoptotic process / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage / oocyte development / B cell apoptotic process / metanephros development / neuron maturation / negative regulation of motor neuron apoptotic process / Regulation of MITF-M-dependent genes involved in apoptosis / positive regulation of multicellular organism growth / regulation of viral genome replication / negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / endoplasmic reticulum calcium ion homeostasis / negative regulation of execution phase of apoptosis / regulation of mitochondrial membrane permeability / fertilization / regulation of growth / calcium ion transport into cytosol / response to UV-B / negative regulation of ossification / response to iron ion / epithelial cell apoptotic process / negative regulation of mitochondrial depolarization / Bcl-2 family protein complex / axon regeneration / motor neuron apoptotic process / positive regulation of smooth muscle cell migration / smooth muscle cell migration / NFE2L2 regulating tumorigenic genes / intrinsic apoptotic signaling pathway in response to oxidative stress / negative regulation of B cell apoptotic process / organ growth / hair follicle morphogenesis / branching involved in ureteric bud morphogenesis / response to cycloheximide / STAT5 activation downstream of FLT3 ITD mutants / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / B cell lineage commitment / negative regulation of G1/S transition of mitotic cell cycle / digestive tract morphogenesis / hepatocyte apoptotic process / detection of maltose stimulus / cellular response to alkaloid / negative regulation of release of cytochrome c from mitochondria / pore complex / maltose transport complex / negative regulation of intrinsic apoptotic signaling pathway / negative regulation of reproductive process / negative regulation of developmental process / germ cell development / apoptotic mitochondrial changes / carbohydrate transport / BH3 domain binding / T cell homeostasis / regulation of calcium ion transport / B cell homeostasis / humoral immune response / B cell proliferation / negative regulation of anoikis / negative regulation of apoptotic signaling pathway / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress
Similarity search - Function
Apoptosis regulator, Bcl-2 / 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 / 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 / Apoptosis regulator proteins, Bcl-2 family / BCL2-like apoptosis inhibitors family profile. / Bcl-2-like superfamily / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / Bacterial extracellular solute-binding protein / Bacterial extracellular solute-binding protein
Similarity search - Domain/homology
Chem-F3Q / DI(HYDROXYETHYL)ETHER / Maltose/maltodextrin-binding periplasmic protein / Apoptosis regulator Bcl-2 / Bcl-2-like protein 1
Similarity search - Component
Biological speciesEscherichia coli K-12 (bacteria)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsBaird, J. / Holliday, M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Anal.Chem. / Year: 2025
Title: Hydrogen/Deuterium Exchange and Protein Oxidative Footprinting with Mass Spectrometry Collectively Discriminate the Binding of Small-Molecule Therapeutics to Bcl-2.
Authors: Sun, Y. / Houde, D. / Iacob, R.E. / Baird, J. / Swift, R.V. / Holliday, M. / Shi, X. / Sidoli, S. / Brenowitz, M.
History
DepositionFeb 5, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 2, 2024Provider: repository / Type: Initial release
Revision 1.1Mar 5, 2025Group: Database references / Structure summary / Category: citation / citation_author / pdbx_entry_details
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _pdbx_entry_details.has_protein_modification
Revision 1.2Mar 12, 2025Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Maltose/maltodextrin-binding periplasmic protein fused to apoptosis regulator Bcl-2/Bcl-xL chimera
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,0783
Polymers61,2611
Non-polymers8172
Water1,22568
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)48.800, 88.740, 134.910
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein Maltose/maltodextrin-binding periplasmic protein fused to apoptosis regulator Bcl-2/Bcl-xL chimera / Bcl2-L-1 / Apoptosis regulator Bcl-X


Mass: 61260.816 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: For the alignment, MBP (UNP P0AEX9, 27-392) spans residues 19-384 (w/ surface entropy reduction mutations at 100, 101, 190, 191, and 257) and is fused to a Bcl-2/Bcl-xL chimera via a linker ...Details: For the alignment, MBP (UNP P0AEX9, 27-392) spans residues 19-384 (w/ surface entropy reduction mutations at 100, 101, 190, 191, and 257) and is fused to a Bcl-2/Bcl-xL chimera via a linker sequence (AARAAA) spanning 385-390. Bcl-2 (UNP P10415, 10-207) has the unstructured loop spanning 35-91 deleted and replaced with Bcl-xL (UNP Q07817, 29-44) for residues 35-50 of the Bcl-2/Bcl-xL chimera, so Bcl-2 spans 391-415 and 432-547, while Bcl-xL spans 416-431. For the 3D model, MBP (-362-3), linker (4-9), Bcl-2 (10-34 and 92-207), and Bcl-xL (35-50). THR88, GLU89, SER90, and GLU91 of the final model correspond to residues 47-50 (Bcl-xL) of the loop replacement (35-50).
Source: (gene. exp.) Escherichia coli K-12 (bacteria), (gene. exp.) Homo sapiens (human)
Strain: K-12 / Gene: malE, b4034, JW3994, BCL2, BCL2L1, BCL2L, BCLX / Plasmid: pET-24b(+) / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P0AEX9, UniProt: P10415, UniProt: Q07817
#2: Chemical ChemComp-F3Q / ~{N}-(4-hydroxyphenyl)-3-[6-[[(3~{S})-3-(morpholin-4-ylmethyl)-3,4-dihydro-1~{H}-isoquinolin-2-yl]carbonyl]-1,3-benzodioxol-5-yl]-~{N}-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamide


Mass: 710.817 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C43H42N4O6 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 68 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.38 Å3/Da / Density % sol: 48.41 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 100 mM Tris (pH 8.5), 25% PEG 3350, 200 mM lithium sulfate

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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 EIGER2 X 9M / Detector: PIXEL / Date: Apr 15, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.035→67.455 Å / Num. obs: 35939 / % possible obs: 93.5 % / Redundancy: 6.6 % / Biso Wilson estimate: 44.02 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.054 / Rpim(I) all: 0.023 / Rrim(I) all: 0.059 / Net I/σ(I): 16.1
Reflection shellResolution: 2.035→2.07 Å / Redundancy: 5.6 % / Rmerge(I) obs: 0.844 / Mean I/σ(I) obs: 1.8 / Num. unique obs: 1390 / CC1/2: 0.855 / Rpim(I) all: 0.382 / Rrim(I) all: 0.93

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
autoPROC1.1.7data reduction
PHASERphasing
autoPROCdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→67.45 Å / SU ML: 0.322 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 31.0819
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2433 1694 5.03 %
Rwork0.2185 31979 -
obs0.2198 33673 96.09 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 55.97 Å2
Refinement stepCycle: LAST / Resolution: 2.1→67.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4051 0 60 68 4179
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00154219
X-RAY DIFFRACTIONf_angle_d0.40535727
X-RAY DIFFRACTIONf_chiral_restr0.0369603
X-RAY DIFFRACTIONf_plane_restr0.0038755
X-RAY DIFFRACTIONf_dihedral_angle_d21.09691563
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.160.3531530.30792705X-RAY DIFFRACTION99.31
2.16-2.230.34061460.29362705X-RAY DIFFRACTION99.41
2.23-2.310.35931040.26982300X-RAY DIFFRACTION83.39
2.31-2.40.31211400.27512718X-RAY DIFFRACTION99.44
2.4-2.510.32531420.25962712X-RAY DIFFRACTION99.51
2.51-2.650.30831520.25392717X-RAY DIFFRACTION99.17
2.65-2.810.27681040.26312053X-RAY DIFFRACTION74
2.81-3.030.29211640.28112714X-RAY DIFFRACTION99.65
3.03-3.330.26081330.26182784X-RAY DIFFRACTION99.83
3.33-3.820.25141430.21232795X-RAY DIFFRACTION99.86
3.82-4.810.21261580.17252818X-RAY DIFFRACTION99.7
4.81-67.450.18311550.18112958X-RAY DIFFRACTION99.52
Refinement TLS params.Method: refined / Origin x: -8.47160108725 Å / Origin y: 7.50239497536 Å / Origin z: -16.326501899 Å
111213212223313233
T0.528722311606 Å2-0.0391870850931 Å2-0.00710673473376 Å2-0.274775055359 Å2-0.0176923176091 Å2--0.547358419366 Å2
L0.517844861461 °2-0.175723519671 °20.0218443906523 °2-1.95166089648 °2-0.746166512851 °2--1.21102067192 °2
S-0.0162669397629 Å °0.0449191822317 Å °-0.00132374469137 Å °-0.253696846085 Å °-0.0477923476229 Å °0.0137874814489 Å °0.150796968811 Å °-0.00906996552643 Å °0.0514168139465 Å °
Refinement TLS groupSelection details: all

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