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- PDB-6gmr: pVHL:EloB:EloC in complex with (4-(1H-pyrrol-1-yl)phenyl)methanol -

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Basic information

Entry
Database: PDB / ID: 6gmr
TitlepVHL:EloB:EloC in complex with (4-(1H-pyrrol-1-yl)phenyl)methanol
Components
  • Elongin-B
  • Elongin-C
  • Hypoxia inducible factor 1alpha, residues 559-577
  • von Hippel-Lindau disease tumor suppressor
KeywordsLIGASE / E3 ubiquitin ligase / von Hippel Lindau tumor supressor / PROTOC / Fragment-based drug discovery
Function / homology
Function and homology information


epithelial cell differentiation involved in mammary gland alveolus development / neural fold elevation formation / iris morphogenesis / positive regulation of chemokine-mediated signaling pathway / hypoxia-inducible factor-1alpha signaling pathway / elastin metabolic process / glandular epithelial cell maturation / regulation of transforming growth factor beta2 production / connective tissue replacement involved in inflammatory response wound healing / cardiac ventricle morphogenesis ...epithelial cell differentiation involved in mammary gland alveolus development / neural fold elevation formation / iris morphogenesis / positive regulation of chemokine-mediated signaling pathway / hypoxia-inducible factor-1alpha signaling pathway / elastin metabolic process / glandular epithelial cell maturation / regulation of transforming growth factor beta2 production / connective tissue replacement involved in inflammatory response wound healing / cardiac ventricle morphogenesis / negative regulation of mesenchymal cell apoptotic process / hemoglobin biosynthetic process / positive regulation of hormone biosynthetic process / mesenchymal cell apoptotic process / positive regulation of mitophagy / retina vasculature development in camera-type eye / Cellular response to hypoxia / intestinal epithelial cell maturation / negative regulation of growth / regulation of protein neddylation / collagen metabolic process / PTK6 Expression / intracellular oxygen homeostasis / regulation of cellular response to hypoxia / negative regulation of bone mineralization / B-1 B cell homeostasis / vascular endothelial growth factor production / RHOBTB3 ATPase cycle / negative regulation of receptor signaling pathway via JAK-STAT / transcription elongation factor activity / transcription regulator activator activity / dopaminergic neuron differentiation / negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / target-directed miRNA degradation / lactate metabolic process / elongin complex / STAT3 nuclear events downstream of ALK signaling / VCB complex / positive regulation of cytokine production involved in inflammatory response / negative regulation of thymocyte apoptotic process / positive regulation of vascular endothelial growth factor receptor signaling pathway / motile cilium / positive regulation of signaling receptor activity / insulin secretion involved in cellular response to glucose stimulus / negative regulation of TOR signaling / response to iron ion / Replication of the SARS-CoV-1 genome / response to muscle activity / Cul5-RING ubiquitin ligase complex / neural crest cell migration / Regulation of gene expression by Hypoxia-inducible Factor / regulation of glycolytic process / embryonic hemopoiesis / Cul2-RING ubiquitin ligase complex / intracellular non-membrane-bounded organelle / DNA-binding transcription repressor activity / DNA-binding transcription activator activity / PTK6 promotes HIF1A stabilization / regulation of aerobic respiration / digestive tract morphogenesis / muscle cell cellular homeostasis / positive regulation of neuroblast proliferation / axonal transport of mitochondrion / SUMOylation of ubiquitinylation proteins / positive regulation of epithelial cell migration / bone mineralization / heart looping / outflow tract morphogenesis / negative regulation of transcription elongation by RNA polymerase II / E-box binding / intracellular glucose homeostasis / positive regulation of insulin secretion involved in cellular response to glucose stimulus / 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 vascular endothelial growth factor production / TOR signaling / neuroblast proliferation / negative regulation of reactive oxygen species metabolic process / embryonic placenta development / Tat-mediated elongation of the HIV-1 transcript / positive regulation of blood vessel endothelial cell migration / epithelial to mesenchymal transition / Formation of HIV-1 elongation complex containing HIV-1 Tat / cellular response to interleukin-1 / cis-regulatory region sequence-specific DNA binding / Formation of HIV elongation complex in the absence of HIV Tat / chondrocyte differentiation / negative regulation of signal transduction / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / positive regulation of chemokine production / axon cytoplasm / negative regulation of TORC1 signaling / positive regulation of endothelial cell proliferation / RNA Polymerase II Pre-transcription Events / lactation / positive regulation of glycolytic process
Similarity search - Function
Hypoxia-inducible factor-1 alpha / von Hippel-Lindau disease tumour suppressor, alpha domain / von Hippel-Lindau disease tumour suppressor, beta domain / Elongin C; Chain C, domain 1 / HIF-1 alpha, transactivation domain, C-terminal / HIF-1 alpha C terminal transactivation domain / Hypoxia-inducible factor, alpha subunit-like / Hypoxia-inducible factor-1 / PAS fold-3 / von Hippel-Lindau disease tumour suppressor, beta/alpha domain ...Hypoxia-inducible factor-1 alpha / von Hippel-Lindau disease tumour suppressor, alpha domain / von Hippel-Lindau disease tumour suppressor, beta domain / Elongin C; Chain C, domain 1 / HIF-1 alpha, transactivation domain, C-terminal / HIF-1 alpha C terminal transactivation domain / Hypoxia-inducible factor, alpha subunit-like / Hypoxia-inducible factor-1 / PAS fold-3 / 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 / PAS fold / Elongin B / Elongin-C / Potassium Channel Kv1.1; Chain A / Potassium Channel Kv1.1; Chain A / PAC motif / Motif C-terminal to PAS motifs (likely to contribute to PAS structural domain) / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / Helix-loop-helix DNA-binding domain superfamily / helix loop helix domain / Myc-type, basic helix-loop-helix (bHLH) domain / Myc-type, basic helix-loop-helix (bHLH) domain profile. / PAS fold / PAS fold / SKP1/BTB/POZ domain superfamily / Phosphatidylinositol 3-kinase Catalytic Subunit; Chain A, domain 1 / PAS domain / PAS repeat profile. / PAS domain / PAS domain superfamily / Ubiquitin-like (UB roll) / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily / Roll / Immunoglobulin-like / Sandwich / 2-Layer Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
(4-pyrrol-1-ylphenyl)methanol / von Hippel-Lindau disease tumor suppressor / Elongin-C / Elongin-B / Hypoxia-inducible factor 1-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.75 Å
AuthorsVan Molle, I. / Lucas, X. / Ciulli, A.
Funding support United Kingdom, 5items
OrganizationGrant numberCountry
European Research CouncilERC-2012-StG-311460
European CommissionH2020-MSCA-IF-2015-806323
European CommissionEC PIEF-GA-2010-275683
welcome trust 100476/Z/12/Z United Kingdom
welcome trust 094090/Z/10/Z United Kingdom
CitationJournal: J. Med. Chem. / Year: 2018
Title: Surface Probing by Fragment-Based Screening and Computational Methods Identifies Ligandable Pockets on the von Hippel-Lindau (VHL) E3 Ubiquitin Ligase.
Authors: Lucas, X. / Van Molle, I. / Ciulli, A.
History
DepositionMay 28, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 8, 2018Provider: repository / Type: Initial release
Revision 1.1Sep 5, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID / _citation_author.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Elongin-B
C: Elongin-C
H: Hypoxia inducible factor 1alpha, residues 559-577
V: von Hippel-Lindau disease tumor suppressor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,5857
Polymers45,2234
Non-polymers3613
Water6,197344
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7010 Å2
ΔGint-60 kcal/mol
Surface area17640 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.880, 59.880, 246.140
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212

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Components

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Protein , 3 types, 3 molecules BCV

#1: 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
#2: 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: 10974.616 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: extra M inserted at the N-terminus by cloning / 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: 18840.438 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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Protein/peptide , 1 types, 1 molecules H

#3: Protein/peptide Hypoxia inducible factor 1alpha, residues 559-577


Mass: 2260.457 Da / Num. of mol.: 1 / Source method: obtained synthetically / Details: residues 559-577 Hyp564 / Source: (synth.) Homo sapiens (human) / References: UniProt: Q16665*PLUS

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Non-polymers , 4 types, 347 molecules

#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#6: Chemical ChemComp-F4K / (4-pyrrol-1-ylphenyl)methanol


Mass: 173.211 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H11NO
#7: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C3H8O3
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 344 / Source method: isolated from a natural source / Formula: H2O

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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: 2.44 Å3/Da / Density % sol: 49.58 %
Crystal growTemperature: 290 K / Method: vapor diffusion, sitting drop
Details: 0.1 M K phosphate pH 6.6, 0.2 M AS, 20% PEG MME 5000, 5% DTT

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 1.07169 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 16, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.07169 Å / Relative weight: 1
ReflectionResolution: 1.75→50 Å / Num. obs: 45106 / % possible obs: 96.5 % / Redundancy: 12.1 % / CC1/2: 1 / Net I/σ(I): 28.69
Reflection shellResolution: 1.75→1.85 Å / Redundancy: 12.5 % / Mean I/σ(I) obs: 2.48 / CC1/2: 0.865 / % possible all: 99.2

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Processing

Software
NameVersionClassification
PHENIX(1.12_2829: ???)refinement
XDSdata reduction
XDSdata scaling
BUSTER-TNTphasing
RefinementResolution: 1.75→33.843 Å / SU ML: 0.23 / Cross valid method: FREE R-VALUE / σ(F): 1.99 / Phase error: 24.92 / Stereochemistry target values: MLHL
RfactorNum. reflection% reflection
Rfree0.2355 2227 5.05 %
Rwork0.211 --
obs0.2122 44124 94.87 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.75→33.843 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2852 0 24 344 3220
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0062974
X-RAY DIFFRACTIONf_angle_d0.8444039
X-RAY DIFFRACTIONf_dihedral_angle_d3.592322
X-RAY DIFFRACTIONf_chiral_restr0.056451
X-RAY DIFFRACTIONf_plane_restr0.005526
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7501-1.78810.29131620.27112680X-RAY DIFFRACTION100
1.7881-1.82970.27461220.26242720X-RAY DIFFRACTION100
1.8297-1.87550.28211410.25712729X-RAY DIFFRACTION100
1.8755-1.92620.4712920.40461540X-RAY DIFFRACTION58
1.9262-1.98280.37341130.30972213X-RAY DIFFRACTION82
1.9828-2.04680.2391530.22992706X-RAY DIFFRACTION100
2.0468-2.120.23741370.22042743X-RAY DIFFRACTION100
2.12-2.20480.26741400.23512732X-RAY DIFFRACTION100
2.2048-2.30520.3491230.31532102X-RAY DIFFRACTION77
2.3052-2.42670.24361310.2252745X-RAY DIFFRACTION100
2.4267-2.57860.291630.21442728X-RAY DIFFRACTION100
2.5786-2.77770.25061260.20962772X-RAY DIFFRACTION100
2.7777-3.0570.23241320.20792807X-RAY DIFFRACTION100
3.057-3.4990.21011740.19422795X-RAY DIFFRACTION100
3.499-4.40680.17931610.18122834X-RAY DIFFRACTION100
4.4068-33.84930.2291570.19073051X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 15.0565 Å / Origin y: -25.4192 Å / Origin z: -5.7195 Å
111213212223313233
T0.2483 Å2-0.0653 Å20.037 Å2-0.2103 Å20.0137 Å2--0.1845 Å2
L1.0932 °2-0.2756 °20.1584 °2-1.115 °20.3527 °2--1.4299 °2
S0.1073 Å °-0.0412 Å °-0.0597 Å °-0.0654 Å °-0.0168 Å °0.0358 Å °-0.0677 Å °-0.0708 Å °-0.0958 Å °
Refinement TLS groupSelection details: all

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