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- PDB-8fy1: E3:PROTAC:target ternary complex structure (VCB/753b/BCL-2) -

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Basic information

Entry
Database: PDB / ID: 8fy1
TitleE3:PROTAC:target ternary complex structure (VCB/753b/BCL-2)
Components
  • Apoptosis regulator Bcl-2
  • Elongin-B
  • Elongin-C
  • von Hippel-Lindau disease tumor suppressor
KeywordsTRANSCRIPTION / ternary complex / degrader
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 cellular response to hypoxia / 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 / RHOBTB3 ATPase cycle / negative regulation of myeloid cell apoptotic process / negative regulation of receptor signaling pathway via JAK-STAT / negative regulation of epithelial cell apoptotic process / regulation of nitrogen utilization / transcription elongation factor activity / 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 / target-directed miRNA degradation / metanephros development / neuron maturation / elongin complex / regulation of viral genome replication / negative regulation of motor neuron apoptotic process / VCB complex / 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 / Replication of the SARS-CoV-1 genome / calcium ion transport into cytosol / channel activity / Cul5-RING ubiquitin ligase complex / negative regulation of mitochondrial depolarization / motor neuron apoptotic process / axon regeneration / epithelial cell apoptotic process / smooth muscle cell migration / Cul2-RING ubiquitin ligase complex / intracellular non-membrane-bounded organelle / 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 / SUMOylation of ubiquitinylation proteins / B cell lineage commitment / pore complex / positive regulation of smooth muscle cell migration / B cell proliferation / negative regulation of transcription elongation by RNA polymerase II / T cell homeostasis / BH3 domain binding / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / regulation of calcium ion transport / B cell homeostasis / negative regulation of apoptotic signaling pathway / humoral immune response / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / negative regulation of anoikis / ubiquitin-like ligase-substrate adaptor activity / 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
Similarity search - Function
Apoptosis regulator, Bcl-2 / von Hippel-Lindau disease tumour suppressor, beta/alpha domain / von Hippel-Lindau disease tumour suppressor, alpha domain / von Hippel-Lindau disease tumour suppressor, beta domain / VHL superfamily / von Hippel-Lindau disease tumour suppressor, alpha domain superfamily / von Hippel-Lindau disease tumour suppressor, beta domain superfamily / VHL beta domain / VHL box domain / Apoptosis regulator, Bcl-2/ BclX ...Apoptosis regulator, Bcl-2 / von Hippel-Lindau disease tumour suppressor, beta/alpha domain / von Hippel-Lindau disease tumour suppressor, alpha domain / von Hippel-Lindau disease tumour suppressor, beta domain / VHL superfamily / von Hippel-Lindau disease tumour suppressor, alpha domain superfamily / von Hippel-Lindau disease tumour suppressor, beta domain superfamily / VHL beta domain / VHL box domain / 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 / Elongin B / Elongin-C / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / 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 / SKP1/BTB/POZ domain superfamily / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily
Similarity search - Domain/homology
: / Apoptosis regulator Bcl-2 / von Hippel-Lindau disease tumor suppressor / Elongin-C / Elongin-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.56 Å
AuthorsNayak, D. / Lv, D. / Yuan, Y. / Zhang, P. / Hu, W. / Lv, Z. / Sung, P. / Hromas, R. / Zheng, G. / Zhou, D. / Olsen, S.K.
Funding support United States, 6items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01 GM115568 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01 GM128731 United States
Cancer Prevention and Research Institute of Texas (CPRIT)RR200030 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R01 CA242003 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R01 CA241191 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)R01 AG063801 United States
CitationJournal: Nat Commun / Year: 2024
Title: Development and crystal structures of a potent second-generation dual degrader of BCL-2 and BCL-xL.
Authors: Nayak, D. / Lv, D. / Yuan, Y. / Zhang, P. / Hu, W. / Nayak, A. / Ruben, E.A. / Lv, Z. / Sung, P. / Hromas, R. / Zheng, G. / Zhou, D. / Olsen, S.K.
History
DepositionJan 25, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 10, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: von Hippel-Lindau disease tumor suppressor
B: Elongin-B
C: Elongin-C
D: Apoptosis regulator Bcl-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,3675
Polymers67,7274
Non-polymers1,6401
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)47.482, 94.593, 81.180
Angle α, β, γ (deg.)90.000, 97.450, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

#1: Protein von Hippel-Lindau disease tumor suppressor / Protein G7 / pVHL


Mass: 20729.531 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: VHL / Production host: Escherichia coli (E. coli) / References: UniProt: P40337
#2: Protein Elongin-B / EloB / Elongin 18 kDa subunit / RNA polymerase II transcription factor SIII subunit B / SIII p18 / ...EloB / Elongin 18 kDa subunit / RNA polymerase II transcription factor SIII subunit B / SIII p18 / Transcription elongation factor B polypeptide 2


Mass: 13147.781 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOB, TCEB2 / Production host: Escherichia coli (E. coli) / References: UniProt: Q15370
#3: Protein Elongin-C / EloC / Elongin 15 kDa subunit / RNA polymerase II transcription factor SIII subunit C / SIII p15 / ...EloC / Elongin 15 kDa subunit / RNA polymerase II transcription factor SIII subunit C / SIII p15 / Transcription elongation factor B polypeptide 1


Mass: 10843.420 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOC, TCEB1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q15369
#4: Protein Apoptosis regulator Bcl-2


Mass: 23005.842 Da / Num. of mol.: 1
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
#5: Chemical ChemComp-YF8 / N-[8-(4-{[(1R,3R,4S)-4-(4-chlorophenyl)-1-methyl-3-{[4-(4-{[4-{[(2R)-4-(morpholin-4-yl)-1-(phenylsulfanyl)butan-2-yl]amino}-3-(trifluoromethanesulfonyl)benzene-1-sulfonyl]carbamoyl}phenyl)piperazin-1-yl]methyl}cyclohexyl]methyl}piperazin-1-yl)-8-oxooctanoyl]-3-methyl-L-valyl-(4R)-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide


Mass: 1640.478 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C82H104ClF3N11O11S4 / Feature type: SUBJECT OF INVESTIGATION
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: 2.67 Å3/Da / Density % sol: 53.92 %
Crystal growTemperature: 291 K / Method: vapor diffusion
Details: 0.1 M Tris-Cl pH 8.7, 18% PEG 8000, 0.2 M MgCl2 and 3% 1,6-Hexanediol

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Data collection

DiffractionMean temperature: 108 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.979 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Nov 29, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.56→94.6 Å / Num. obs: 22772 / % possible obs: 99.1 % / Redundancy: 6.9 % / Biso Wilson estimate: 55.35 Å2 / CC1/2: 0.99 / Net I/σ(I): 12.2
Reflection shellResolution: 2.56→2.68 Å / Num. unique obs: 2722 / CC1/2: 0.8

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6DC6

6dc6


Resolution: 2.56→80.5 Å / SU ML: 0.3737 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 30.2062
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.25 1997 8.8 %
Rwork0.2122 20692 -
obs0.2156 22689 98.77 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 66.25 Å2
Refinement stepCycle: LAST / Resolution: 2.56→80.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3915 0 112 0 4027
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00574134
X-RAY DIFFRACTIONf_angle_d0.76835620
X-RAY DIFFRACTIONf_chiral_restr0.059601
X-RAY DIFFRACTIONf_plane_restr0.0048719
X-RAY DIFFRACTIONf_dihedral_angle_d15.50291544
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.56-2.630.33711390.30361438X-RAY DIFFRACTION93.42
2.63-2.70.31491410.28121450X-RAY DIFFRACTION98.94
2.7-2.780.36711420.31891488X-RAY DIFFRACTION98.97
2.78-2.870.3821400.3311448X-RAY DIFFRACTION98.57
2.87-2.970.33291420.27751463X-RAY DIFFRACTION97.51
2.97-3.090.30371410.2491454X-RAY DIFFRACTION99.69
3.09-3.230.32311440.26451495X-RAY DIFFRACTION99.76
3.23-3.40.33611450.28421506X-RAY DIFFRACTION99.64
3.4-3.610.32091410.22931468X-RAY DIFFRACTION99.81
3.61-3.890.27841440.21541488X-RAY DIFFRACTION99.51
3.89-4.280.18771440.18711492X-RAY DIFFRACTION98.49
4.28-4.90.16151430.15481473X-RAY DIFFRACTION99.94
4.9-6.180.23981440.17411506X-RAY DIFFRACTION99.88
6.18-80.50.18821470.16481523X-RAY DIFFRACTION98.93

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