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- PDB-6gfx: pVHL:EloB:EloC in complex with modified HIF-1a CODD peptide conta... -

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Basic information

Entry
Database: PDB / ID: 6gfx
TitlepVHL:EloB:EloC in complex with modified HIF-1a CODD peptide containing (3R,4S)-3-fluoro-4-hydroxyproline (ligand 13a)
Components
  • Elongin-B
  • Elongin-C
  • FLUORINATED HYPOXIA-INDUCIBLE FACTOR 1 ALPHA PEPTIDE
  • von Hippel-Lindau disease tumor suppressor
KeywordsLIGASE / PROTEIN-PEPTIDE COMPLEX / UBIQUITIN LIGASE / HYPOXIA INDUCIBLE FACTOR
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 / Cellular response to hypoxia / retina vasculature development in camera-type eye / 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 / lactate metabolic process / transcription elongation factor activity / negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / transcription regulator activator activity / dopaminergic neuron differentiation / target-directed miRNA degradation / 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 / motile cilium / positive regulation of vascular endothelial growth factor receptor signaling pathway / positive regulation of signaling receptor activity / insulin secretion involved in cellular response to glucose stimulus / response to iron ion / negative regulation of TOR signaling / response to muscle activity / Replication of the SARS-CoV-1 genome / 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 / DNA-binding transcription repressor activity / regulation of aerobic respiration / DNA-binding transcription activator activity / PTK6 promotes HIF1A stabilization / digestive tract morphogenesis / muscle cell cellular homeostasis / positive regulation of neuroblast proliferation / axonal transport of mitochondrion / intracellular non-membrane-bounded organelle / positive regulation of epithelial cell migration / SUMOylation of ubiquitinylation proteins / heart looping / bone mineralization / outflow tract morphogenesis / E-box binding / negative regulation of transcription elongation by RNA polymerase II / 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 / TOR signaling / neuroblast proliferation / positive regulation of vascular endothelial growth factor production / negative regulation of reactive oxygen species metabolic process / embryonic placenta development / epithelial to mesenchymal transition / Tat-mediated elongation of the HIV-1 transcript / positive regulation of blood vessel endothelial cell migration / Formation of HIV-1 elongation complex containing HIV-1 Tat / cellular response to interleukin-1 / cis-regulatory region sequence-specific DNA binding / chondrocyte differentiation / Formation of HIV elongation complex in the absence of HIV Tat / 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
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: 1.83 Å
AuthorsCastro, G.V. / Testa, A. / Ciulli, A.
Funding support1items
OrganizationGrant numberCountry
European Research CouncilERC-2012-StG-311460 DrugE3CRLs
CitationJournal: J. Am. Chem. Soc. / Year: 2018
Title: 3-Fluoro-4-hydroxyprolines: Synthesis, Conformational Analysis, and Stereoselective Recognition by the VHL E3 Ubiquitin Ligase for Targeted Protein Degradation.
Authors: Testa, A. / Lucas, X. / Castro, G.V. / Chan, K.H. / Wright, J.E. / Runcie, A.C. / Gadd, M.S. / Harrison, W.T.A. / Ko, E.J. / Fletcher, D. / Ciulli, A.
History
DepositionMay 2, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 11, 2018Provider: repository / Type: Initial release
Revision 1.1Aug 1, 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
A: Elongin-B
B: Elongin-C
C: von Hippel-Lindau disease tumor suppressor
D: FLUORINATED HYPOXIA-INDUCIBLE FACTOR 1 ALPHA PEPTIDE


Theoretical massNumber of molelcules
Total (without water)43,5444
Polymers43,5444
Non-polymers00
Water5,062281
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: isothermal titration calorimetry, Peptide binds to the VHL-elonginB-elonginC complex with a dissociation constant of 12 nM., gel filtration, VHL-ElonginB-ElonginC were co-expressed then ...Evidence: isothermal titration calorimetry, Peptide binds to the VHL-elonginB-elonginC complex with a dissociation constant of 12 nM., gel filtration, VHL-ElonginB-ElonginC were co-expressed then mixed with the chemically synthesized peptide. Mixture is purified as a monomeric fully assembled complex
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6690 Å2
ΔGint-46 kcal/mol
Surface area17380 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.258, 59.258, 245.337
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212

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Components

#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: 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 BL21 (bacteria) / 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
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOC, TCEB1 / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: Q15369
#3: Protein von Hippel-Lindau disease tumor suppressor / Protein G7 / pVHL


Mass: 18558.162 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 BL21 (bacteria) / References: UniProt: P40337
#4: Protein/peptide FLUORINATED HYPOXIA-INDUCIBLE FACTOR 1 ALPHA PEPTIDE


Mass: 2262.448 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q16665*PLUS
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 281 / 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: 2.47 Å3/Da / Density % sol: 50.19 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 20-22% PEG MME 5000, 0.2 M ammonium sulfate, 0.1 M potassium phosphate, 10 mM DTT
PH range: 6.0 - 6.2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9763 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Dec 18, 2016
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 1.83→61.33 Å / Num. obs: 39987 / % possible obs: 100 % / Redundancy: 17 % / CC1/2: 0.999 / Rmerge(I) obs: 0.095 / Rpim(I) all: 0.024 / Rrim(I) all: 0.098 / Net I/σ(I): 17.8
Reflection shellResolution: 1.83→1.87 Å / Redundancy: 15.2 % / Rmerge(I) obs: 1.083 / Num. unique obs: 2427 / CC1/2: 0.87 / Rpim(I) all: 0.286 / Rrim(I) all: 1.121 / % possible all: 99.9

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Processing

Software
NameVersionClassification
Aimless0.5.9data scaling
REFMACrefinement
PDB_EXTRACT3.24data extraction
XDSdata reduction
REFMACphasing
RefinementResolution: 1.83→61.33 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.948 / SU B: 4.574 / SU ML: 0.07 / SU R Cruickshank DPI: 0.1195 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.12 / ESU R Free: 0.113
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2124 1841 4.6 %RANDOM
Rwork0.1832 ---
obs0.1846 38034 99.96 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 87.12 Å2 / Biso mean: 31.778 Å2 / Biso min: 12.13 Å2
Baniso -1Baniso -2Baniso -3
1-0.07 Å2-0 Å2-0 Å2
2--0.07 Å2-0 Å2
3----0.13 Å2
Refinement stepCycle: final / Resolution: 1.83→61.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2846 0 0 281 3127
Biso mean---44.76 -
Num. residues----355
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0192922
X-RAY DIFFRACTIONr_bond_other_d0.0020.022745
X-RAY DIFFRACTIONr_angle_refined_deg1.4321.9853966
X-RAY DIFFRACTIONr_angle_other_deg0.9393.0026368
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.855352
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.5423.309136
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.1415503
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.5941526
X-RAY DIFFRACTIONr_chiral_restr0.0820.2448
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0213194
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02592
LS refinement shellResolution: 1.83→1.877 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.261 116 -
Rwork0.215 2755 -
all-2871 -
obs--99.79 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.01251.04770.34361.3380.19430.66910.0752-0.03640.05190.1203-0.02110.03840.03330.005-0.05410.10380.01540.0090.0468-0.01830.024146.912764.286186.5489
20.7662-0.0663-0.18051.04090.22620.91750.01930.02720.057-0.00120.02730.0918-0.0078-0.0303-0.04660.03930.01260.00210.04460.01330.017735.978759.040773.5381
30.9470.2553-0.41080.4002-0.1650.7341-0.01680.1179-0.0225-0.0482-0.0129-0.02490.0895-0.03970.02970.07270.0224-0.00090.0457-0.00450.003148.421945.651951.9341
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 104
2X-RAY DIFFRACTION2B17 - 112
3X-RAY DIFFRACTION3C61 - 207
4X-RAY DIFFRACTION3D560 - 575

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