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- PDB-4ux8: RET recognition of GDNF-GFRalpha1 ligand by a composite binding s... -

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Basic information

Entry
Database: PDB / ID: 4ux8
TitleRET recognition of GDNF-GFRalpha1 ligand by a composite binding site promotes membrane-proximal self-association
Components
  • GDNF FAMILY RECEPTOR ALPHA-1
  • GLIAL CELL LINE-DERIVED NEUROTROPHIC FACTOR
  • PROTO-ONCOGENE TYROSINE-PROTEIN KINASE RECEPTOR RET
KeywordsSIGNALING PROTEIN / VERTEBRATE DEVELOPMENT / HUMAN DISEASES / PART OF THE RET-GFL- GFRA COMPLEX
Function / homology
Function and homology information


chemoattractant activity involved in axon guidance / 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 / glial cell-derived neurotrophic factor receptor activity / glial cell-derived neurotrophic factor receptor binding ...chemoattractant activity involved in axon guidance / 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 / glial cell-derived neurotrophic factor receptor activity / glial cell-derived neurotrophic factor receptor binding / RET signaling / postsynaptic membrane organization / Peyer's patch morphogenesis / GDF15-GFRAL signaling pathway / positive regulation of metanephric glomerulus development / embryonic epithelial tube formation / ureter maturation / glial cell-derived neurotrophic factor receptor signaling pathway / lymphocyte migration into lymphoid organs / posterior midgut development / regulation of morphogenesis of a branching structure / neurotrophin receptor activity / regulation of dopamine uptake involved in synaptic transmission / Formation of the ureteric bud / membrane protein proteolysis / Formation of the nephric duct / peristalsis / enteric nervous system development / neuron cell-cell adhesion / positive regulation of dopamine secretion / sympathetic nervous system development / positive regulation of branching involved in ureteric bud morphogenesis / organ induction / peripheral nervous system development / plasma membrane protein complex / commissural neuron axon guidance / metanephros development / NCAM1 interactions / neuron maturation / regulation of stem cell differentiation / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / mRNA stabilization / positive regulation of cell adhesion mediated by integrin / RAF/MAP kinase cascade / neural crest cell migration / ureteric bud development / positive regulation of peptidyl-tyrosine phosphorylation / regulation of axonogenesis / branching involved in ureteric bud morphogenesis / response to pain / homophilic cell-cell adhesion / RET signaling / positive regulation of cell size / embryonic organ development / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / regulation of cell adhesion / side of membrane / cellular response to retinoic acid / NPAS4 regulates expression of target genes / multivesicular body / transmembrane receptor protein tyrosine kinase activity / axon guidance / cell surface receptor protein tyrosine kinase signaling pathway / adult locomotory behavior / positive regulation of cell differentiation / growth factor activity / kidney development / positive regulation of neuron projection development / receptor protein-tyrosine kinase / receptor tyrosine kinase binding / male gonad development / integrin binding / neuron differentiation / neuron projection development / cell migration / nervous system development / MAPK cascade / signaling receptor activity / regulation of gene expression / RAF/MAP kinase cascade / protein tyrosine kinase activity / negative regulation of neuron apoptotic process / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / positive regulation of MAPK cascade / endosome membrane / positive regulation of cell migration / signaling receptor binding / axon / external side of plasma membrane / neuronal cell body / positive regulation of cell population proliferation / calcium ion binding / positive regulation of gene expression / negative regulation of apoptotic process / positive regulation of DNA-templated transcription / Golgi apparatus / signal transduction / protein homodimerization activity / positive regulation of transcription by RNA polymerase II
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 family / Glial cell line-derived neurotrophic factor receptor / GDNF receptor alpha / 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 family / Glial cell line-derived neurotrophic factor receptor / GDNF receptor alpha / 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 / RET, Cysteine Rich Domain / 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 / Cadherin-like / Cadherins domain profile. / 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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-1 / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / negative staining / Resolution: 24 Å
AuthorsGoodman, K. / Kjaer, S. / Beuron, F. / Knowles, P. / Nawrotek, A. / Burns, E. / Purkiss, A. / George, R. / Santoro, M. / Morris, E.P. / McDonald, N.Q.
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
DepositionAug 19, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 1, 2014Provider: repository / Type: Initial release
Revision 1.1Oct 8, 2014Group: Database references
Revision 1.2Aug 23, 2017Group: Data collection / Category: em_software / Item: _em_software.image_processing_id
Revision 1.3Oct 23, 2019Group: Data collection / Derived calculations / Other / Category: cell / struct_conn / Item: _cell.Z_PDB / _struct_conn.pdbx_leaving_atom_flag
Revision 2.0Jul 29, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / database_PDB_caveat / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / pdbx_struct_conn_angle / struct_asym / struct_conn / struct_conn_type / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.type_symbol / _chem_comp.name / _chem_comp.type / _entity.formula_weight / _entity.pdbx_description / _entity.pdbx_number_of_molecules / _entity.src_method / _entity.type / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_conn_type.id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Oct 23, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_entry_details.has_protein_modification

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Structure visualization

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  • Deposited structure unit
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Assembly

Deposited unit
A: PROTO-ONCOGENE TYROSINE-PROTEIN KINASE RECEPTOR RET
B: PROTO-ONCOGENE TYROSINE-PROTEIN KINASE RECEPTOR RET
C: GDNF FAMILY RECEPTOR ALPHA-1
D: GLIAL CELL LINE-DERIVED NEUROTROPHIC FACTOR
E: GDNF FAMILY RECEPTOR ALPHA-1
F: GLIAL CELL LINE-DERIVED NEUROTROPHIC FACTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)269,30914
Polymers268,2206
Non-polymers1,0898
Water00
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA

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Components

#1: Protein PROTO-ONCOGENE TYROSINE-PROTEIN KINASE RECEPTOR RET / CADHERIN FAMILY MEMBER 12 / PROTO-ONCOGENE C-RET / RET RECEPTOR TYROSINE KINASE


Mass: 67922.539 Da / Num. of mol.: 2 / Fragment: RET EXTRACELLULAR DOMAIN, RESIDUES 29-635 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): CHO LEC8 / Production host: CRICETULUS GRISEUS (Chinese hamster)
References: UniProt: P07949, receptor protein-tyrosine kinase
#2: Protein GDNF FAMILY RECEPTOR ALPHA-1 / GFR ALPHA 1


Mass: 51091.277 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) RATTUS NORVEGICUS (Norway rat) / Cell line (production host): CHO LEC8 / Production host: CRICETULUS GRISEUS (Chinese hamster) / References: UniProt: O35748, UniProt: Q62997*PLUS
#3: Protein GLIAL CELL LINE-DERIVED NEUROTROPHIC FACTOR / HGDNF / ASTROCYTE-DERIVED TROPHIC FACTOR / ATF / GDNF


Mass: 15096.242 Da / Num. of mol.: 2 / Fragment: MATURE, UNP RESIDUES 78-211
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P39905
#4: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#5: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Ca
Has protein modificationY
Sequence detailsRESIDUES 509 TO 635 ARE NOT IN THE MODEL

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Reconstituted mammalian RETecd-GDNF-GFRa1 ternary complex
Type: COMPLEX
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: YES / Vitrification applied: NO
EM stainingType: NEGATIVE / Material: uranyl acetate

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Electron microscopy imaging

Experimental equipment
Model: Tecnai F20 / Image courtesy: FEI Company
MicroscopyModel: FEI TECNAI F20 / Date: Nov 8, 2012
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: OTHER / Nominal magnification: 80000 X / Nominal defocus min: 900 nm
Image recordingElectron dose: 100 e/Å2 / Film or detector model: TVIPS TEMCAM-F415 (4k x 4k)
Image scansNum. digital images: 1200
Radiation wavelengthRelative weight: 1

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Processing

EM software
IDNameCategory
1Custom3D reconstruction
2IMAGIC3D reconstruction
3SPIDER3D reconstruction
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionMethod: ANGULAR RECONSTITUTION / Resolution: 24 Å / Num. of particles: 8519
Details: SUBMISSION BASED ON EXPERIMENTAL DATA FROM EMDB EMD-2712. (DEPOSITION ID: 12696).
Symmetry type: POINT
RefinementHighest resolution: 24 Å
Refinement stepCycle: LAST / Highest resolution: 24 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12984 0 62 0 13046

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