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- PDB-7ab8: Crystal structure of a GDNF-GFRalpha1 complex -

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Basic information

Entry
Database: PDB / ID: 7ab8
TitleCrystal structure of a GDNF-GFRalpha1 complex
Components
  • GDNF family receptor alphaGFRα
  • Glial cell line-derived neurotrophic factor
KeywordsSIGNALING PROTEIN / VERTEBRATE DEVELOPMENT / PART OF THE RET-GFL-GFRA COMPLEX / NEUROTROPHIC FACTOR
Function / homology
Function and homology information


RAF/MAP kinase cascade / : / diencephalon development / positive regulation of ureteric bud formation / postganglionic parasympathetic fiber development / positive regulation of monooxygenase activity / regulation of dopaminergic neuron differentiation / glial cell-derived neurotrophic factor receptor binding / regulation of morphogenesis of a branching structure / regulation of dopamine uptake involved in synaptic transmission ...RAF/MAP kinase cascade / : / diencephalon development / positive regulation of ureteric bud formation / postganglionic parasympathetic fiber development / positive regulation of monooxygenase activity / regulation of dopaminergic neuron differentiation / glial cell-derived neurotrophic factor receptor binding / regulation of morphogenesis of a branching structure / regulation of dopamine uptake involved in synaptic transmission / enteric nervous system development / positive regulation of branching involved in ureteric bud morphogenesis / peristalsis / sympathetic nervous system development / peripheral nervous system development / mRNA stabilization / metanephros development / neural crest cell migration / branching involved in ureteric bud morphogenesis / MAP kinase kinase kinase activity / growth factor activity / receptor tyrosine kinase binding / neuron projection development / signaling receptor activity / nervous system development / protein-containing complex assembly / negative regulation of neuron apoptotic process / receptor complex / external side of plasma membrane / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / extracellular space / extracellular region
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 / Transforming growth factor-beta, C-terminal / Transforming growth factor beta like domain / TGF-beta family profile. / Cystine-knot cytokine
Similarity search - Domain/homology
DI(HYDROXYETHYL)ETHER / GDNF family receptor alpha / Glial cell line-derived neurotrophic factor
Similarity search - Component
Biological speciesDanio rerio (zebrafish)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsAdams, S.E. / Earl, C.P. / Purkiss, A.G. / McDonald, N.Q.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
The Francis Crick Institute10115 United Kingdom
CitationJournal: Structure / Year: 2021
Title: A two-site flexible clamp mechanism for RET-GDNF-GFRα1 assembly reveals both conformational adaptation and strict geometric spacing.
Authors: Sarah E Adams / Andrew G Purkiss / Phillip P Knowles / Andrea Nans / David C Briggs / Annabel Borg / Christopher P Earl / Kerry M Goodman / Agata Nawrotek / Aaron J Borg / Pauline B McIntosh ...Authors: Sarah E Adams / Andrew G Purkiss / Phillip P Knowles / Andrea Nans / David C Briggs / Annabel Borg / Christopher P Earl / Kerry M Goodman / Agata Nawrotek / Aaron J Borg / Pauline B McIntosh / Francesca M Houghton / Svend Kjær / Neil Q McDonald /
Abstract: RET receptor tyrosine kinase plays vital developmental and neuroprotective roles in metazoans. GDNF family ligands (GFLs) when bound to cognate GFRα co-receptors recognize and activate RET ...RET receptor tyrosine kinase plays vital developmental and neuroprotective roles in metazoans. GDNF family ligands (GFLs) when bound to cognate GFRα co-receptors recognize and activate RET stimulating its cytoplasmic kinase function. The principles for RET ligand-co-receptor recognition are incompletely understood. Here, we report a crystal structure of the cadherin-like module (CLD1-4) from zebrafish RET revealing interdomain flexibility between CLD2 and CLD3. Comparison with a cryo-electron microscopy structure of a ligand-engaged zebrafish RET-GDNF-GFRα1a complex indicates conformational changes within a clade-specific CLD3 loop adjacent to the co-receptor. Our observations indicate that RET is a molecular clamp with a flexible calcium-dependent arm that adapts to different GFRα co-receptors, while its rigid arm recognizes a GFL dimer to align both membrane-proximal cysteine-rich domains. We also visualize linear arrays of RET-GDNF-GFRα1a suggesting that a conserved contact stabilizes higher-order species. Our study reveals that ligand-co-receptor recognition by RET involves both receptor plasticity and strict spacing of receptor dimers by GFL ligands.
History
DepositionSep 7, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 13, 2021Provider: repository / Type: Initial release
Revision 1.1Feb 3, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jul 14, 2021Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.page_first
Revision 1.3Jan 31, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: GDNF family receptor alpha
B: Glial cell line-derived neurotrophic factor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,91413
Polymers34,6482
Non-polymers1,26511
Water3,945219
1
A: GDNF family receptor alpha
B: Glial cell line-derived neurotrophic factor
hetero molecules

A: GDNF family receptor alpha
B: Glial cell line-derived neurotrophic factor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,82726
Polymers69,2974
Non-polymers2,53122
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_565-x,-y+1,z1
Unit cell
Length a, b, c (Å)125.067, 55.544, 70.961
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Space group name HallP22ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x+1/2,y+1/2,-z
#4: -x,-y,z

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein GDNF family receptor alpha / GFRα


Mass: 23366.529 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Danio rerio (zebrafish) / Gene: gfra1a, gfralpha1a / Plasmid: pBacPAK-LL-zGFRa1a1-352-3C-ProteinA / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): IPLB-Sf21-AE / References: UniProt: Q98TT9
#2: Protein Glial cell line-derived neurotrophic factor / / zGDNF


Mass: 11281.832 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Danio rerio (zebrafish) / Gene: gdnf / Plasmid: pBacPAK-LL-melittin-zGDNFmat.-3C-ProteinA / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): IPLB-Sf21-AE / References: UniProt: Q98TU0

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Sugars , 1 types, 1 molecules

#3: 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.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam 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
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE

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Non-polymers , 3 types, 229 molecules

#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C4H10O3
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 219 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN

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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: 2.61 Å3/Da / Density % sol: 52.94 %
Crystal growTemperature: 295 K / Method: vapor diffusion / pH: 8 / Details: Tris, PEG 20K, MeCN, NaCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Jun 26, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.2→50.78 Å / Num. obs: 25823 / % possible obs: 91.93 % / Redundancy: 2 % / Biso Wilson estimate: 20.87 Å2 / CC1/2: 0.997 / CC star: 0.999 / Rmerge(I) obs: 0.05616 / Rpim(I) all: 0.05616 / Rrim(I) all: 0.07942 / Net I/σ(I): 12.3
Reflection shellResolution: 2.2→2.279 Å / Redundancy: 2 % / Rmerge(I) obs: 0.3711 / Mean I/σ(I) obs: 3.15 / Num. unique obs: 1368 / CC1/2: 0.797 / CC star: 0.942 / Rpim(I) all: 0.3711 / Rrim(I) all: 0.5247 / % possible all: 53.94

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
DIALSdata processing
Cootmodel building
STARANISOdata processing
PHASERphasing
DIALSdata reduction
DIALSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3FUB

3fub


Resolution: 2.2→50.76 Å / SU ML: 0.2217 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 22.6954
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2302 1152 4.85 %
Rwork0.199 22591 -
obs0.2006 23743 91.95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 30.19 Å2
Refinement stepCycle: LAST / Resolution: 2.2→50.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2408 0 83 219 2710
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00642556
X-RAY DIFFRACTIONf_angle_d0.74723429
X-RAY DIFFRACTIONf_chiral_restr0.0559376
X-RAY DIFFRACTIONf_plane_restr0.004447
X-RAY DIFFRACTIONf_dihedral_angle_d24.104982
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.30.2598840.23331869X-RAY DIFFRACTION61.57
2.3-2.420.27651480.22322956X-RAY DIFFRACTION98.07
2.42-2.570.24961510.21543026X-RAY DIFFRACTION99.97
2.57-2.770.25551430.21452539X-RAY DIFFRACTION84.05
2.77-3.050.22791630.19883041X-RAY DIFFRACTION100
3.05-3.490.22011400.19952897X-RAY DIFFRACTION93.76
3.49-4.40.23641670.17722999X-RAY DIFFRACTION97.39
4.4-50.760.19241560.19263264X-RAY DIFFRACTION99.91

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