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- PDB-8g1q: Co-crystal structure of Compound 1 in complex with the bromodomai... -

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Entry
Database: PDB / ID: 8g1q
TitleCo-crystal structure of Compound 1 in complex with the bromodomain of human SMARCA4 and pVHL:ElonginC:ElonginB
Components
  • Elongin-B
  • Elongin-C
  • Transcription activator BRG1
  • von Hippel-Lindau disease tumor suppressor
KeywordsGENE REGULATION / Ternary Complex / PROTACs / TRANSCRIPTION
Function / homology
Function and homology information


positive regulation of glucose mediated signaling pathway / bBAF complex / positive regulation of transcription of nucleolar large rRNA by RNA polymerase I / npBAF complex / negative regulation of androgen receptor signaling pathway / Tat protein binding / nBAF complex / regulation of cellular response to hypoxia / GBAF complex / neural retina development ...positive regulation of glucose mediated signaling pathway / bBAF complex / positive regulation of transcription of nucleolar large rRNA by RNA polymerase I / npBAF complex / negative regulation of androgen receptor signaling pathway / Tat protein binding / nBAF complex / regulation of cellular response to hypoxia / GBAF complex / neural retina development / regulation of G0 to G1 transition / EGR2 and SOX10-mediated initiation of Schwann cell myelination / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / nucleosome disassembly / transcription elongation factor activity / regulation of nucleotide-excision repair / target-directed miRNA degradation / elongin complex / RSC-type complex / VCB complex / RNA polymerase I preinitiation complex assembly / positive regulation by host of viral transcription / regulation of mitotic metaphase/anaphase transition / ATP-dependent chromatin remodeler activity / Replication of the SARS-CoV-1 genome / SWI/SNF complex / positive regulation of double-strand break repair / Cul5-RING ubiquitin ligase complex / positive regulation of T cell differentiation / Cul2-RING ubiquitin ligase complex / intracellular non-membrane-bounded organelle / nuclear androgen receptor binding / positive regulation of stem cell population maintenance / SUMOylation of ubiquitinylation proteins / RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known / negative regulation of transcription elongation by RNA polymerase II / regulation of G1/S transition of mitotic cell cycle / negative regulation of cell differentiation / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / ubiquitin-like ligase-substrate adaptor activity / positive regulation of Wnt signaling pathway / Tat-mediated elongation of the HIV-1 transcript / Formation of HIV-1 elongation complex containing HIV-1 Tat / positive regulation of myoblast differentiation / ATP-dependent activity, acting on DNA / Formation of HIV elongation complex in the absence of HIV Tat / Chromatin modifying enzymes / negative regulation of signal transduction / DNA polymerase binding / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / transcription initiation-coupled chromatin remodeling / negative regulation of TORC1 signaling / RNA Polymerase II Pre-transcription Events / Interleukin-7 signaling / negative regulation of autophagy / helicase activity / transcription corepressor binding / transcription coregulator binding / transcription elongation by RNA polymerase II / positive regulation of cell differentiation / transcription initiation at RNA polymerase II promoter / TP53 Regulates Transcription of DNA Repair Genes / Vif-mediated degradation of APOBEC3G / Formation of the beta-catenin:TCF transactivating complex / Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement / lysine-acetylated histone binding / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / cell morphogenesis / Inactivation of CSF3 (G-CSF) signaling / Evasion by RSV of host interferon responses / negative regulation of cell growth / fibrillar center / kinetochore / RMTs methylate histone arginines / Regulation of expression of SLITs and ROBOs / positive regulation of DNA-binding transcription factor activity / nuclear matrix / positive regulation of miRNA transcription / ubiquitin-protein transferase activity / transcription corepressor activity / Antigen processing: Ubiquitination & Proteasome degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / p53 binding / protein-macromolecule adaptor activity / Neddylation / nervous system development / positive regulation of cold-induced thermogenesis / Replication of the SARS-CoV-2 genome / cellular response to hypoxia / ubiquitin-dependent protein catabolic process / regulation of gene expression / protein-containing complex assembly / proteasome-mediated ubiquitin-dependent protein catabolic process / DNA-binding transcription factor binding / amyloid fibril formation
Similarity search - Function
SWI/SNF complex subunit BRG1 / BRK domain / BRK domain / BRK domain superfamily / domain in transcription and CHROMO domain helicases / domain in helicases and associated with SANT domains / Glutamine-Leucine-Glutamine, QLQ / QLQ / QLQ domain profile. / QLQ ...SWI/SNF complex subunit BRG1 / BRK domain / BRK domain / BRK domain superfamily / domain in transcription and CHROMO domain helicases / domain in helicases and associated with SANT domains / Glutamine-Leucine-Glutamine, QLQ / QLQ / QLQ domain profile. / QLQ / Snf2, ATP coupling domain / Snf2-ATP coupling, chromatin remodelling complex / Snf2-ATP coupling, chromatin remodelling complex / HSA domain / 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 / Helicase/SANT-associated domain / HSA domain profile. / Elongin B / Elongin-C / : / SNF2-like, N-terminal domain superfamily / SNF2, N-terminal / SNF2-related domain / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / SKP1/BTB/POZ domain superfamily / Helicase conserved C-terminal domain / Bromodomain, conserved site / Bromodomain signature. / Ubiquitin family / Bromodomain / Ubiquitin homologues / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Ubiquitin domain profile. / Ubiquitin-like domain / helicase superfamily c-terminal domain / Superfamilies 1 and 2 helicase C-terminal domain profile. / Superfamilies 1 and 2 helicase ATP-binding type-1 domain profile. / DEAD-like helicases superfamily / Helicase, C-terminal / Helicase superfamily 1/2, ATP-binding domain / Ubiquitin-like domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
DI(HYDROXYETHYL)ETHER / Chem-YHB / von Hippel-Lindau disease tumor suppressor / Transcription activator BRG1 / Elongin-C / Elongin-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.73 Å
AuthorsGhimire Rijal, S. / Wurz, R.P. / Vaish, A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2023
Title: Affinity and cooperativity modulate ternary complex formation to drive targeted protein degradation.
Authors: Wurz, R.P. / Rui, H. / Dellamaggiore, K. / Ghimire-Rijal, S. / Choi, K. / Smither, K. / Amegadzie, A. / Chen, N. / Li, X. / Banerjee, A. / Chen, Q. / Mohl, D. / Vaish, A.
History
DepositionFeb 2, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 26, 2023Provider: repository / Type: Initial release
Revision 1.1Aug 30, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Item: _pdbx_initial_refinement_model.type

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: Transcription activator BRG1
A: Elongin-B
B: Elongin-C
C: von Hippel-Lindau disease tumor suppressor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,7687
Polymers55,8204
Non-polymers9483
Water724
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)158.163, 158.163, 44.857
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number171
Space group name H-MP62

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Components

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Protein , 4 types, 4 molecules HABC

#1: Protein Transcription activator BRG1 / ATP-dependent helicase SMARCA4 / BRG1-associated factor 190A / BAF190A / Mitotic growth and ...ATP-dependent helicase SMARCA4 / BRG1-associated factor 190A / BAF190A / Mitotic growth and transcription activator / Protein BRG-1 / Protein brahma homolog 1 / SNF2-beta / SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4


Mass: 14525.742 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SMARCA4, BAF190A, BRG1, SNF2B, SNF2L4 / Production host: Escherichia coli (E. coli)
References: UniProt: P51532, Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement
#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: 11748.406 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 von Hippel-Lindau disease tumor suppressor / Protein G7 / pVHL


Mass: 18702.291 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

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Non-polymers , 4 types, 7 molecules

#5: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#6: Chemical ChemComp-YHB / N-(2-{4-[(6M)-3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]piperazin-1-yl}pyridine-4-carbonyl)-3-methyl-L-valyl-(4R)-4-hydroxy-N-{(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide


Mass: 818.986 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C43H50N10O5S
#7: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


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


Mass: 18.015 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.77 Å3/Da / Density % sol: 55.67 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: PEG 300 0.1M Bis-Tris 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: May 20, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.73→45.66 Å / Num. obs: 6928 / % possible obs: 99.88 % / Redundancy: 10.8 % / CC1/2: 0.99 / Rrim(I) all: 0.366 / Net I/σ(I): 7.7
Reflection shellResolution: 3.73→4.17 Å / Redundancy: 10.1 % / Rmerge(I) obs: 0.065 / Num. unique obs: 6944 / CC1/2: 0.99

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.73→45.66 Å / SU ML: 0.59 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 33.85 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.3258 346 4.99 %
Rwork0.2347 --
obs0.2395 6928 99.88 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3.73→45.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3399 0 67 4 3470
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0043558
X-RAY DIFFRACTIONf_angle_d0.7554825
X-RAY DIFFRACTIONf_dihedral_angle_d14.289482
X-RAY DIFFRACTIONf_chiral_restr0.046542
X-RAY DIFFRACTIONf_plane_restr0.007622
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.73-4.70.36011690.25353236X-RAY DIFFRACTION100
4.7-45.660.30421770.22223346X-RAY DIFFRACTION100

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