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- EMDB-2712: Structure of the RET receptor tyrosine kinase extracellular domain -

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Basic information

Entry
Database: EMDB / ID: EMD-2712
TitleStructure of the RET receptor tyrosine kinase extracellular domain
Map dataReconstruction of a reconstituted mammalian RETecd-GDNF-GFRa1 ternary (mTC) complex
Sample
  • Sample: Reconstituted mammalian RETecd-GDNF-GFRa1 ternary complex
  • Protein or peptide: RET receptor tyrosine kinase
  • Protein or peptide: GDNF receptor alphaGFRα
  • Protein or peptide: glial-cell-line-derived neurotrophic factor
Keywordsvertebrate development / human diseases / RET-GFL-GFRa complex
Function / homology
Function and homology information


chemoattractant activity involved in axon guidance / postsynaptic membrane organization / mesenchymal to epithelial transition involved in metanephros morphogenesis / dorsal spinal cord development / positive regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis / ureteric bud formation / positive regulation of ureteric bud formation / regulation of semaphorin-plexin signaling pathway / postganglionic parasympathetic fiber development / positive regulation of monooxygenase activity ...chemoattractant activity involved in axon guidance / postsynaptic membrane organization / mesenchymal to epithelial transition involved in metanephros morphogenesis / dorsal spinal cord development / positive regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis / ureteric bud formation / positive regulation of ureteric bud formation / regulation of semaphorin-plexin signaling pathway / postganglionic parasympathetic fiber development / positive regulation of monooxygenase activity / glial cell-derived neurotrophic factor receptor binding / RET signaling / glial cell-derived neurotrophic factor receptor signaling pathway / Peyer's patch morphogenesis / positive regulation of metanephric glomerulus development / posterior midgut development / ureter maturation / embryonic epithelial tube formation / : / lymphocyte migration into lymphoid organs / regulation of morphogenesis of a branching structure / neurotrophin receptor activity / membrane protein proteolysis / regulation of dopamine uptake involved in synaptic transmission / positive regulation of peptidyl-serine phosphorylation of STAT protein / positive regulation of neuron maturation / neuron cell-cell adhesion / enteric nervous system development / positive regulation of branching involved in ureteric bud morphogenesis / peristalsis / positive regulation of dopamine secretion / sympathetic nervous system development / innervation / peripheral nervous system development / organ induction / plasma membrane protein complex / regulation of stem cell differentiation / mRNA stabilization / neuron maturation / commissural neuron axon guidance / metanephros development / NCAM1 interactions / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / RAF/MAP kinase cascade / positive regulation of cell adhesion mediated by integrin / neural crest cell migration / ureteric bud development / response to pain / branching involved in ureteric bud morphogenesis / regulation of axonogenesis / homophilic cell adhesion via plasma membrane adhesion molecules / positive regulation of cell size / RET signaling / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / embryonic organ development / regulation of cell adhesion / cellular response to retinoic acid / NPAS4 regulates expression of target genes / transmembrane receptor protein tyrosine kinase activity / multivesicular body / adult locomotory behavior / kidney development / axon guidance / positive regulation of cell differentiation / growth factor activity / positive regulation of neuron projection development / receptor tyrosine kinase binding / neuron differentiation / receptor protein-tyrosine kinase / male gonad development / neuron projection development / cell surface receptor protein tyrosine kinase signaling pathway / activation of cysteine-type endopeptidase activity involved in apoptotic process / MAPK cascade / positive regulation of peptidyl-tyrosine phosphorylation / cell migration / integrin binding / retina development in camera-type eye / signaling receptor activity / nervous system development / RAF/MAP kinase cascade / regulation of gene expression / protein tyrosine kinase activity / negative regulation of neuron apoptotic process / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / early endosome / receptor complex / endosome membrane / positive regulation of cell migration / response to xenobiotic stimulus / axon / external side of plasma membrane / signaling receptor binding / protein phosphorylation / neuronal cell body / dendrite / calcium ion binding / positive regulation of cell population proliferation / positive regulation of gene expression
Similarity search - Function
: / Glial cell line-derived neurotrophic factor receptor, alpha 1 / Glial cell line-derived neurotrophic factor / Glial cell line-derived neurotrophic factor receptor, alpha 1/2 / Glial cell line-derived neurotrophic factor receptor / GDNF receptor alpha / Glial cell line-derived neurotrophic factor family / GDNF/GAS1 / GDNF/GAS1 domain / GDNF/GAS1 domain ...: / Glial cell line-derived neurotrophic factor receptor, alpha 1 / Glial cell line-derived neurotrophic factor / Glial cell line-derived neurotrophic factor receptor, alpha 1/2 / Glial cell line-derived neurotrophic factor receptor / GDNF receptor alpha / Glial cell line-derived neurotrophic factor family / GDNF/GAS1 / GDNF/GAS1 domain / GDNF/GAS1 domain / Tyrosine-protein kinase, Ret receptor / Tyrosine-protein kinase receptor Ret, cadherin like domain 3 / Ret, cadherin like domain 1 / RET, cadherin-like domain 4 / RET Cadherin like domain 1 / RET Cadherin like domain 3 / RET Cadherin like domain 4 / Transforming growth factor-beta (TGF-beta) family / Transforming growth factor-beta, C-terminal / Transforming growth factor beta like domain / TGF-beta family profile. / Cadherin domain / Cadherins domain profile. / Cadherin-like / Cadherin-like superfamily / Cystine-knot cytokine / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
GDNF family receptor alpha / Proto-oncogene tyrosine-protein kinase receptor Ret / Glial cell line-derived neurotrophic factor / GDNF family receptor alpha-1
Similarity search - Component
Biological speciesHomo sapiens (human) / Rattus norvegicus (Norway rat)
Methodsingle particle reconstruction / negative staining / Resolution: 24.0 Å
AuthorsGoodman K / Kjaer S / Beuron F / Knowles P / Nawrotek A / Burns E / Purkiss A / George R / Santoro M / Morris EP / McDonald NQ
CitationJournal: Cell Rep / Year: 2014
Title: RET recognition of GDNF-GFRα1 ligand by a composite binding site promotes membrane-proximal self-association.
Authors: Kerry M Goodman / Svend Kjær / Fabienne Beuron / Phillip P Knowles / Agata Nawrotek / Emily M Burns / Andrew G Purkiss / Roger George / Massimo Santoro / Edward P Morris / Neil Q McDonald /
Abstract: The RET receptor tyrosine kinase is essential to vertebrate development and implicated in multiple human diseases. RET binds a cell surface bipartite ligand comprising a GDNF family ligand and a ...The RET receptor tyrosine kinase is essential to vertebrate development and implicated in multiple human diseases. RET binds a cell surface bipartite ligand comprising a GDNF family ligand and a GFRα coreceptor, resulting in RET transmembrane signaling. We present a hybrid structural model, derived from electron microscopy (EM) and low-angle X-ray scattering (SAXS) data, of the RET extracellular domain (RET(ECD)), GDNF, and GFRα1 ternary complex, defining the basis for ligand recognition. RET(ECD) envelopes the dimeric ligand complex through a composite binding site comprising four discrete contact sites. The GFRα1-mediated contacts are crucial, particularly close to the invariant RET calcium-binding site, whereas few direct contacts are made by GDNF, explaining how distinct ligand/coreceptor pairs are accommodated. The RET(ECD) cysteine-rich domain (CRD) contacts both ligand components and makes homotypic membrane-proximal interactions occluding three different antibody epitopes. Coupling of these CRD-mediated interactions suggests models for ligand-induced RET activation and ligand-independent oncogenic deregulation.
History
DepositionJul 17, 2014-
Header (metadata) releaseJul 23, 2014-
Map releaseOct 1, 2014-
UpdateOct 8, 2014-
Current statusOct 8, 2014Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 2.42
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 2.42
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-4ux8
  • Surface level: 2.42
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

EMD-2712.png

Downloads & links

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Map

FileDownload / File: emd_2712.map.gz / Format: CCP4 / Size: 3.3 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationReconstruction of a reconstituted mammalian RETecd-GDNF-GFRa1 ternary (mTC) complex
Voxel sizeX=Y=Z: 4.34 Å
Density
Contour LevelBy AUTHOR: 2.42 / Movie #1: 2.42
Minimum - Maximum-19.55950928 - 26.869428630000002
Average (Standard dev.)0.0 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-48-48-48
Dimensions969696
Spacing969696
CellA=B=C: 416.64 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z4.344.344.34
M x/y/z969696
origin x/y/z0.0000.0000.000
length x/y/z416.640416.640416.640
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ442626
MAP C/R/S123
start NC/NR/NS-48-48-48
NC/NR/NS969696
D min/max/mean-19.56026.869-0.000

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Supplemental data

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Sample components

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Entire : Reconstituted mammalian RETecd-GDNF-GFRa1 ternary complex

EntireName: Reconstituted mammalian RETecd-GDNF-GFRa1 ternary complex
Components
  • Sample: Reconstituted mammalian RETecd-GDNF-GFRa1 ternary complex
  • Protein or peptide: RET receptor tyrosine kinase
  • Protein or peptide: GDNF receptor alphaGFRα
  • Protein or peptide: glial-cell-line-derived neurotrophic factor

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Supramolecule #1000: Reconstituted mammalian RETecd-GDNF-GFRa1 ternary complex

SupramoleculeName: Reconstituted mammalian RETecd-GDNF-GFRa1 ternary complex
type: sample / ID: 1000
Details: Monodisperse. Measured mass difference with theoretical MW corresponds to glycosylation.
Oligomeric state: Hexamer / Number unique components: 3
Molecular weightExperimental: 340 KDa / Theoretical: 260 KDa / Method: SEC-MALS

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Macromolecule #1: RET receptor tyrosine kinase

MacromoleculeName: RET receptor tyrosine kinase / type: protein_or_peptide / ID: 1 / Name.synonym: RET / Number of copies: 2 / Recombinant expression: Yes
Source (natural)Organism: Homo sapiens (human) / synonym: Human
Molecular weightTheoretical: 80 KDa
Recombinant expressionOrganism: Chinese Hamster Ovary (Chinese hamster) / Recombinant strain: Lec8

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Macromolecule #2: GDNF receptor alpha

MacromoleculeName: GDNF receptor alpha / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Recombinant expression: Yes
Source (natural)Organism: Rattus norvegicus (Norway rat) / synonym: rat
Molecular weightTheoretical: 40 KDa
Recombinant expressionOrganism: Chinese Hamster Ovary (Chinese hamster)

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Macromolecule #3: glial-cell-line-derived neurotrophic factor

MacromoleculeName: glial-cell-line-derived neurotrophic factor / type: protein_or_peptide / ID: 3 / Name.synonym: GDNF / Details: from Amgen (USA) / Number of copies: 2 / Recombinant expression: Yes
Source (natural)Organism: Homo sapiens (human) / synonym: Human
Molecular weightTheoretical: 10 KDa

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Experimental details

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Structure determination

Methodnegative staining
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.03 mg/mL
BufferpH: 8 / Details: 20 mM Tris HCl, 300 mM NaCl, 1 mM Ca++
StainingType: NEGATIVE
Details: Samples were applied to glow-discharged grids and stained with 2% uranyl acetate
GridDetails: quantifoil (R1.2/1.3) coated with a thin carbon layer, glow discharge in air.
VitrificationCryogen name: NONE / Instrument: OTHER

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Electron microscopy

MicroscopeFEI TECNAI F20
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus min: 0.9 µm / Nominal magnification: 80000
Sample stageSpecimen holder model: SIDE ENTRY, EUCENTRIC
DateNov 8, 2012
Image recordingCategory: CCD / Film or detector model: TVIPS TEMCAM-F415 (4k x 4k) / Number real images: 1200 / Average electron dose: 100 e/Å2 / Bits/pixel: 16
Experimental equipment
Model: Tecnai F20 / Image courtesy: FEI Company

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Image processing

Final two d classificationNumber classes: 975
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Algorithm: OTHER / Resolution.type: BY AUTHOR / Resolution: 24.0 Å / Resolution method: OTHER / Software - Name: IMAGIC, SPIDER, in-house, software / Number images used: 8519
DetailsThe particles were selected manually. The starting model was calculated from reference-free classes using angular reconstitution methods and further refined by projection matching.

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