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- PDB-8ymb: The crystal structure of SHD931 in complex with Brd4-BD2 and VCB -

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Basic information

Entry
Database: PDB / ID: 8ymb
TitleThe crystal structure of SHD931 in complex with Brd4-BD2 and VCB
Components
  • Bromodomain-containing protein 4
  • Elongin-B
  • Elongin-C
  • von Hippel-Lindau disease tumor suppressor
KeywordsLIGASE / Complex / Protac / Macrocyclic
Function / homology
Function and homology information


regulation of cellular response to hypoxia / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / target-directed miRNA degradation / transcription elongation factor activity / VCB complex / elongin complex / Replication of the SARS-CoV-1 genome / Cul5-RING ubiquitin ligase complex / intracellular membraneless organelle ...regulation of cellular response to hypoxia / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / target-directed miRNA degradation / transcription elongation factor activity / VCB complex / elongin complex / Replication of the SARS-CoV-1 genome / Cul5-RING ubiquitin ligase complex / intracellular membraneless organelle / Cul2-RING ubiquitin ligase complex / SUMOylation of ubiquitinylation proteins / negative regulation of transcription elongation by RNA polymerase II / RNA polymerase II C-terminal domain binding / P-TEFb complex binding / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / negative regulation of DNA damage checkpoint / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / negative regulation by host of viral transcription / Tat-mediated elongation of the HIV-1 transcript / ubiquitin-like ligase-substrate adaptor activity / Formation of HIV-1 elongation complex containing HIV-1 Tat / negative regulation of signal transduction / positive regulation of T-helper 17 cell lineage commitment / Formation of HIV elongation complex in the absence of HIV Tat / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / negative regulation of TORC1 signaling / protein serine/threonine kinase binding / positive regulation of G2/M transition of mitotic cell cycle / RNA Polymerase II Pre-transcription Events / RNA polymerase II CTD heptapeptide repeat kinase activity / negative regulation of autophagy / condensed nuclear chromosome / transcription corepressor binding / histone reader activity / : / positive regulation of transcription elongation by RNA polymerase II / positive regulation of cell differentiation / transcription coregulator activity / TP53 Regulates Transcription of DNA Repair Genes / transcription initiation at RNA polymerase II promoter / transcription elongation by RNA polymerase II / Vif-mediated degradation of APOBEC3G / Inactivation of CSF3 (G-CSF) signaling / cell morphogenesis / Evasion by RSV of host interferon responses / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Regulation of expression of SLITs and ROBOs / ubiquitin-protein transferase activity / transcription corepressor activity / p53 binding / Antigen processing: Ubiquitination & Proteasome degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Neddylation / chromosome / microtubule cytoskeleton / regulation of gene expression / Replication of the SARS-CoV-2 genome / protein-containing complex assembly / ubiquitin-dependent protein catabolic process / regulation of inflammatory response / protein-macromolecule adaptor activity / DNA-binding transcription factor binding / molecular adaptor activity / cellular response to hypoxia / histone binding / amyloid fibril formation / proteasome-mediated ubiquitin-dependent protein catabolic process / Potential therapeutics for SARS / positive regulation of canonical NF-kappaB signal transduction / transcription coactivator activity / transcription cis-regulatory region binding / protein stabilization / protein ubiquitination / cilium / chromatin remodeling / negative regulation of cell population proliferation / negative regulation of gene expression / protein serine/threonine kinase activity / ubiquitin protein ligase binding / DNA damage response / chromatin binding / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / chromatin / positive regulation of DNA-templated transcription / enzyme binding / negative regulation of transcription by RNA polymerase II / endoplasmic reticulum / positive regulation of transcription by RNA polymerase II / mitochondrion / proteolysis / nucleoplasm / nucleus / plasma membrane / cytosol
Similarity search - Function
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 / Elongin-C / Elongin B ...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 / Elongin-C / Elongin B / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / Brdt, bromodomain, repeat I / Brdt, bromodomain, repeat II / NET domain superfamily / NET domain profile. / : / NET domain / Bromodomain extra-terminal - transcription regulation / SKP1/BTB/POZ domain superfamily / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily
Similarity search - Domain/homology
: / Bromodomain-containing protein 4 / von Hippel-Lindau disease tumor suppressor / Elongin-C / Elongin-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.95 Å
AuthorsHuang, W.X. / Chen, Y.H. / Li, C.G. / Ding, K.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32071446 China
CitationJournal: Jacs Au / Year: 2024
Title: Structure-Based Design of "Head-to-Tail" Macrocyclic PROTACs.
Authors: Li, C. / Chen, Y. / Huang, W. / Qiu, Y. / Huang, S. / Zhou, Y. / Zhou, F. / Xu, J. / Ren, X. / Zhang, J. / Wang, Z. / Ding, M. / Ding, K.
History
DepositionMar 8, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 12, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Bromodomain-containing protein 4
B: Elongin-B
C: Elongin-C
D: von Hippel-Lindau disease tumor suppressor
F: Bromodomain-containing protein 4
G: Elongin-B
H: Elongin-C
I: von Hippel-Lindau disease tumor suppressor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)117,93818
Polymers115,6738
Non-polymers2,26410
Water23413
1
A: Bromodomain-containing protein 4
B: Elongin-B
C: Elongin-C
D: von Hippel-Lindau disease tumor suppressor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)59,00410
Polymers57,8374
Non-polymers1,1686
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
F: Bromodomain-containing protein 4
G: Elongin-B
H: Elongin-C
I: von Hippel-Lindau disease tumor suppressor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,9338
Polymers57,8374
Non-polymers1,0974
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)84.061, 84.388, 382.717
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Space group name HallC2c2
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z+1/2
#4: -x,-y,z+1/2
#5: x+1/2,y+1/2,z
#6: x+1/2,-y+1/2,-z
#7: -x+1/2,y+1/2,-z+1/2
#8: -x+1/2,-y+1/2,z+1/2
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1(chain "A" and ((resid 350 and (name N or name...
d_2ens_1(chain "F" and (resid 350 through 422 or (resid 423...
d_1ens_2(chain "B" and (resid 1 through 45 or (resid 46...
d_2ens_2(chain "G" and (resid 1 through 35 or (resid 36...
d_1ens_3(chain "C" and (resid 16 through 47 or resid 58...
d_2ens_3(chain "H" and (resid 16 through 88 or (resid 89...
d_1ens_4(chain "D" and (resid 62 through 63 or (resid 64...
d_2ens_4(chain "I" and (resid 62 through 72 or (resid 73...

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_11ens_1VALVALMETMETAA350 - 45718 - 125
d_21ens_1VALVALMETMETFE350 - 45718 - 125
d_11ens_2METMETLYSLYSBB1 - 1045 - 108
d_21ens_2METMETLYSLYSGF1 - 1045 - 108
d_11ens_3SERSERSERSERCC16 - 472 - 33
d_12ens_3ASNASNCYSCYSCC58 - 11244 - 98
d_21ens_3SERSERCYSCYSHG16 - 1122 - 98
d_11ens_4VALVALLEULEUDD62 - 14010 - 88
d_12ens_4PROPROHISHISDD146 - 20894 - 156
d_21ens_4VALVALHISHISIH62 - 20810 - 156

NCS ensembles :
ID
ens_1
ens_2
ens_3
ens_4

NCS oper:
IDCodeMatrixVector
1given(-0.00252555373573, 0.999993176957, 0.00269585200994), (0.999995557639, 0.00252980928767, -0.00157631440589), (-0.00158312364208, 0.00269185896725, -0.999995123796)-42.1335671693, -0.0302800184562, -95.7346053271
2given(0.00366211261758, 0.999992994474, 0.000774554506628), (0.999990946496, -0.00366378139712, 0.00216417018481), (0.00216699282205, 0.000766622059255, -0.999997358213)-41.9935287869, 0.114563630527, -95.7035069375
3given(0.00123385435621, 0.999999228841, -0.000141140507636), (0.999999237236, -0.00123384644543, 5.61223111655E-5), (5.59481221726E-5, -0.000141209646737, -0.999999988465)-42.0330484708, 0.00790163664996, -95.6765298761
4given(-0.00686280935314, 0.999972058152, 0.00296391009389), (0.999975893617, 0.00686590387289, -0.00103515664171), (-0.00105547763931, 0.00295673456206, -0.999995071832)-41.9817522642, -0.214614739102, -95.7409939395

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Components

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Protein , 4 types, 8 molecules AFBGCHDI

#1: Protein Bromodomain-containing protein 4 / Protein HUNK1


Mass: 14842.058 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: O60885
#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: 13436.042 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOB, TCEB2 / Production host: Escherichia coli BL21(DE3) (bacteria) / 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: 10987.550 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOC, TCEB1 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q15369
#4: Protein von Hippel-Lindau disease tumor suppressor / Protein G7 / pVHL


Mass: 18571.096 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: VHL / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P40337

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Non-polymers , 3 types, 23 molecules

#5: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Formula: Cl
#6: Chemical ChemComp-A1LY0 / SHD931


Mass: 990.286 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C53H67N9O6S2 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 13 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.85 Å3/Da / Density % sol: 56.81 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 1500 mM Ammonium sulfate, 100 mM Tris base/ Hydrochloric acid, pH 8.5, 12% (v/v) Glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL10U2 / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jan 22, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.95→47.84 Å / Num. obs: 29155 / % possible obs: 99.41 % / Redundancy: 5.2 % / Biso Wilson estimate: 72.98 Å2 / CC1/2: 0.994 / Rmerge(I) obs: 0.16 / Net I/σ(I): 10.55
Reflection shellResolution: 2.95→3.055 Å / Rmerge(I) obs: 1.085 / Mean I/σ(I) obs: 1.85 / Num. unique obs: 2837 / CC1/2: 0.615

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5T35

5t35


Resolution: 2.95→47.84 Å / SU ML: 0.3797 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 29.2758
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2702 2004 6.89 %
Rwork0.2396 27092 -
obs0.2417 29096 99.44 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 76.51 Å2
Refinement stepCycle: LAST / Resolution: 2.95→47.84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6992 0 148 13 7153
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00427311
X-RAY DIFFRACTIONf_angle_d0.62359937
X-RAY DIFFRACTIONf_chiral_restr0.04521103
X-RAY DIFFRACTIONf_plane_restr0.00431276
X-RAY DIFFRACTIONf_dihedral_angle_d12.50262679
Refine LS restraints NCS
Ens-IDDom-IDAsym-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AAX-RAY DIFFRACTIONTorsion NCS0.49225335941
ens_2d_2BBX-RAY DIFFRACTIONTorsion NCS0.714434705039
ens_3d_2CCX-RAY DIFFRACTIONTorsion NCS0.527187096021
ens_4d_2DDX-RAY DIFFRACTIONTorsion NCS0.56735773628
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.95-3.020.35531370.31841931X-RAY DIFFRACTION100
3.02-3.110.34181410.30551908X-RAY DIFFRACTION99.95
3.11-3.20.32351430.29921888X-RAY DIFFRACTION99.85
3.2-3.30.37791440.28771951X-RAY DIFFRACTION100
3.3-3.420.29371360.27231894X-RAY DIFFRACTION99.75
3.42-3.550.3381420.29281933X-RAY DIFFRACTION99.95
3.55-3.720.29341450.25471940X-RAY DIFFRACTION99.76
3.72-3.910.28421420.24321920X-RAY DIFFRACTION99.85
3.91-4.160.29541410.2221911X-RAY DIFFRACTION99.52
4.16-4.480.21271430.21611936X-RAY DIFFRACTION99.62
4.48-4.930.25341480.20991961X-RAY DIFFRACTION99.43
4.93-5.640.27621420.23231939X-RAY DIFFRACTION99.52
5.64-7.10.30561470.25221993X-RAY DIFFRACTION99.67
7.1-47.840.19511530.2021987X-RAY DIFFRACTION95.54
Refinement TLS params.Method: refined / Origin x: -10.2537043538 Å / Origin y: 10.6872948703 Å / Origin z: -47.7150809948 Å
111213212223313233
T0.509969049558 Å20.0888672021095 Å20.073175283152 Å2-0.448404544007 Å2-0.0677644322965 Å2--0.727715828072 Å2
L0.30952582773 °20.127622368575 °2-0.0915142650385 °2-0.328222678112 °20.0145774628701 °2--0.272147705367 °2
S-0.00493770802346 Å °0.0337744605157 Å °0.0614935062908 Å °0.00492657060071 Å °0.0512676249717 Å °-0.0487676400879 Å °0.0178161374061 Å °0.0159048107842 Å °-0.0559235903882 Å °
Refinement TLS groupSelection details: all

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