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- PDB-7lhb: Crystal structure of Bcl-2 in complex with prodrug ABBV-167 -

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Basic information

Entry
Database: PDB / ID: 7lhb
TitleCrystal structure of Bcl-2 in complex with prodrug ABBV-167
ComponentsApoptosis regulator Bcl-2
KeywordsAPOPTOSIS / Bcl-2 / prodrug / ABBV-167
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 B cell apoptotic process / negative regulation of ossification / 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 / 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 / positive regulation of smooth muscle cell migration / B cell proliferation / pore complex / BH3 domain binding / T cell homeostasis / 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 / ossification / axonogenesis / negative regulation of cell migration / negative regulation of autophagy / 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-XZD / Apoptosis regulator Bcl-2
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.068 Å
AuthorsJudge, R.A. / Salem, A.H.
CitationJournal: Mol.Cancer Ther. / Year: 2021
Title: Expanding the Repertoire for "Large Small Molecules": Prodrug ABBV-167 Efficiently Converts to Venetoclax with Reduced Food Effect in Healthy Volunteers.
Authors: Salem, A.H. / Tao, Z.F. / Bueno, O.F. / Chen, J. / Chen, S. / Edalji, R. / Elmore, S.W. / Fournier, K.M. / Harper, K.C. / Hong, R. / Jenkins, G.J. / Ji, J. / Judge, R.A. / Kalvass, J.C. / ...Authors: Salem, A.H. / Tao, Z.F. / Bueno, O.F. / Chen, J. / Chen, S. / Edalji, R. / Elmore, S.W. / Fournier, K.M. / Harper, K.C. / Hong, R. / Jenkins, G.J. / Ji, J. / Judge, R.A. / Kalvass, J.C. / Klix, R.C. / Ku, Y.Y. / Leverson, J.D. / Marks, R.A. / Marsh, K.C. / Menon, R.M. / Park, C.H. / Phillips, D.C. / Pu, Y.M. / Rosenberg, S.H. / Sanzgiri, Y.D. / Sheikh, A.Y. / Shi, Y. / Stolarik, D. / Suleiman, A.A. / Wang, X. / Zhang, G.G.Z. / Catron, N.D. / Souers, A.J.
History
DepositionJan 21, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 14, 2021Provider: repository / Type: Initial release
Revision 1.1Jun 16, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 2.0Apr 13, 2022Group: Database references / Non-polymer description / Structure summary
Category: chem_comp / database_2 / entity
Item: _chem_comp.formula / _chem_comp.formula_weight ..._chem_comp.formula / _chem_comp.formula_weight / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.formula_weight
Revision 2.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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
C: Apoptosis regulator Bcl-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,0026
Polymers58,0673
Non-polymers2,9353
Water3,693205
1
A: Apoptosis regulator Bcl-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,3342
Polymers19,3561
Non-polymers9781
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Apoptosis regulator Bcl-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,3342
Polymers19,3561
Non-polymers9781
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Apoptosis regulator Bcl-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,3342
Polymers19,3561
Non-polymers9781
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)62.362, 49.448, 89.359
Angle α, β, γ (deg.)90, 103.63, 90
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Apoptosis regulator Bcl-2


Mass: 19355.580 Da / Num. of mol.: 3 / Fragment: UNP residues 35-91 replaced with DVEENRTEAPEGTESE / Mutation: A4P, R26K
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) synthetic construct (others)
Gene: BCL2 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P10415
#2: Chemical ChemComp-XZD / Phosphoric acid mono-[5-(5-{4-[2-(4-chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-2-{3-nitro-4-[(tetrahydro-pyran-4-ylmethyl)-amino]-benzenesulfonylaminocarbonyl}-phenoxy)-pyrrolo[2,3-b]pyridin-7-ylmethyl] ester


Mass: 978.445 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C46H53ClN7O11PS / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 205 / 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: 2.31 Å3/Da / Density % sol: 46.66 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 20% w/v PEG4000, 0.1 M Tris-HCl, pH 8.0, 0.2 M calcium chloride

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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: ADSC QUANTUM 210 / Detector: CCD / Date: Aug 9, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.068→60.61 Å / Num. obs: 32544 / % possible obs: 99.5 % / Redundancy: 3.4 % / CC1/2: 0.998 / Rmerge(I) obs: 0.054 / Net I/σ(I): 12.9
Reflection shellResolution: 2.068→2.104 Å / Num. unique obs: 1588 / CC1/2: 0.733

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSBuilt 20191015data reduction
XDSdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 4LVT

4lvt


Resolution: 2.068→60.61 Å / Cor.coef. Fo:Fc: 0.915 / Cor.coef. Fo:Fc free: 0.91 / SU R Cruickshank DPI: 0.195 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.197 / SU Rfree Blow DPI: 0.167 / SU Rfree Cruickshank DPI: 0.167
RfactorNum. reflection% reflectionSelection details
Rfree0.2378 1607 -RANDOM
Rwork0.2025 ---
obs0.2042 32544 99.5 %-
Displacement parametersBiso mean: 51.33 Å2
Baniso -1Baniso -2Baniso -3
1--19.3137 Å20 Å2-11.4027 Å2
2--9.9266 Å20 Å2
3---9.3871 Å2
Refine analyzeLuzzati coordinate error obs: 0.31 Å
Refinement stepCycle: LAST / Resolution: 2.068→60.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3383 0 201 205 3789
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0083699HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.815026HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1306SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes737HARMONIC5
X-RAY DIFFRACTIONt_it3699HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion407SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact3137SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.98
X-RAY DIFFRACTIONt_other_torsion16.71
LS refinement shellResolution: 2.07→2.08 Å
RfactorNum. reflection% reflection
Rfree0.3325 38 -
Rwork0.2689 --
obs0.2726 651 99.68 %

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