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- PDB-9hyt: Crystal structure of the GFRaL receptor in complex with an inhibi... -

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Basic information

Entry
Database: PDB / ID: 9hyt
TitleCrystal structure of the GFRaL receptor in complex with an inhibitory cyclic peptide
Components
  • GDNF family receptor alpha-like
  • Inhibitory cyclic peptide
KeywordsSIGNALING PROTEIN / GFRaL / GFRalpha-like / GDF15 / RET / inhibitor
Function / homology
Function and homology information


response to metformin / glial cell-derived neurotrophic factor receptor activity / reduction of food intake in response to dietary excess / GDF15-GFRAL signaling pathway / negative regulation of appetite / stress-activated protein kinase signaling cascade / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / hormone activity / receptor tyrosine kinase binding / nervous system development ...response to metformin / glial cell-derived neurotrophic factor receptor activity / reduction of food intake in response to dietary excess / GDF15-GFRAL signaling pathway / negative regulation of appetite / stress-activated protein kinase signaling cascade / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / hormone activity / receptor tyrosine kinase binding / nervous system development / signaling receptor activity / actin cytoskeleton / negative regulation of neuron apoptotic process / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / positive regulation of MAPK cascade / external side of plasma membrane / focal adhesion / nucleoplasm / plasma membrane
Similarity search - Function
Glial cell line-derived neurotrophic factor receptor / GDNF receptor alpha / GDNF/GAS1 / GDNF/GAS1 domain / GDNF/GAS1 domain
Similarity search - Domain/homology
Chem-29N / ACETIC ACID / GDNF family receptor alpha-like
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsSandmark, J. / Ek, M.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: J.Med.Chem. / Year: 2025
Title: Design of Bicyclic Peptide Tandems Mimicking the Homodimeric GDF15 Protein to Inhibit GDF15–GFRaL–RET Complex Cell Signaling
Authors: Noisier, A.F.M. / Sandmark, J. / Edfeldt, F. / Backmark, A. / Broddefalk, J. / Wandzik, J. / Jurva, U. / Ek, M. / Johansson, C.A. / Barlind, L. / Gunnarsson, J. / Bigalke, J.M. / Xue, Y. / ...Authors: Noisier, A.F.M. / Sandmark, J. / Edfeldt, F. / Backmark, A. / Broddefalk, J. / Wandzik, J. / Jurva, U. / Ek, M. / Johansson, C.A. / Barlind, L. / Gunnarsson, J. / Bigalke, J.M. / Xue, Y. / Frolov, A.I. / Kankkonen, C. / Roth, R.G. / Fritsch, M. / Watcham, S. / van Rietschoten, K. / Mudd, G.E. / Harrison, H. / Chen, L. / Skynner, M.J. / Craik, D.J. / Chankeshwara, S.V. / Lemurell, M.
History
DepositionJan 10, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 22, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: GDNF family receptor alpha-like
B: GDNF family receptor alpha-like
C: GDNF family receptor alpha-like
D: Inhibitory cyclic peptide
E: Inhibitory cyclic peptide
F: Inhibitory cyclic peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)89,87217
Polymers88,3736
Non-polymers1,49811
Water5,873326
1
A: GDNF family receptor alpha-like
D: Inhibitory cyclic peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,9055
Polymers29,4582
Non-polymers4473
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: GDNF family receptor alpha-like
E: Inhibitory cyclic peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,0617
Polymers29,4582
Non-polymers6045
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: GDNF family receptor alpha-like
F: Inhibitory cyclic peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,9055
Polymers29,4582
Non-polymers4473
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)59.541, 148.183, 198.053
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21A
32A
42A
53A
63A

NCS domain segments:

End auth comp-ID: THR / End label comp-ID: THR / Auth asym-ID: A / Label asym-ID: A

Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDAuth seq-IDLabel seq-ID
111TRPTRP129 - 32123 - 215
211TRPTRP129 - 32123 - 215
322GLYGLY127 - 32121 - 215
422GLYGLY127 - 32121 - 215
533TRPTRP129 - 32123 - 215
633TRPTRP129 - 32123 - 215

NCS ensembles :
IDDetails
1Local NCS retraints between domains: 1 2
2Local NCS retraints between domains: 3 4
3Local NCS retraints between domains: 5 6

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Components

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Protein / Protein/peptide , 2 types, 6 molecules ABCDEF

#1: Protein GDNF family receptor alpha-like


Mass: 27665.693 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GFRAL, C6orf144, UNQ9356/PRO34128 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q6UXV0
#2: Protein/peptide Inhibitory cyclic peptide


Mass: 1792.112 Da / Num. of mol.: 3 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 4 types, 337 molecules

#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-ACY / ACETIC ACID


Mass: 60.052 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H4O2
#5: Chemical ChemComp-29N / 1,1',1''-(1,3,5-triazinane-1,3,5-triyl)tripropan-1-one / 1,1',1''-(1,3,5-triazinane-1,3,5-triyl)triprop-2-en-1-one, bound form


Mass: 255.313 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C12H21N3O3 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 326 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 2.45 Å3/Da / Density % sol: 49.83 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.3 M (NH4)2SO4, 0.1 M Na-citrate, 0.9 M LiSO4 100nL GFRaL-peptide mixture mixed with 80nL well solution and 20nL seed stock.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.98 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Oct 24, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.9→99 Å / Num. obs: 38664 / % possible obs: 92.5 % / Redundancy: 3.5 % / CC1/2: 0.999 / Net I/σ(I): 11.2
Reflection shellResolution: 1.9→2.19 Å / Num. unique obs: 11748 / CC1/2: 0.669

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Processing

Software
NameVersionClassification
REFMAC5.8.0352refinement
autoPROCdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→99 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.918 / SU B: 5.283 / SU ML: 0.14 / Cross valid method: FREE R-VALUE / ESU R: 0.271 / ESU R Free: 0.22
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflectionSelection details
Rfree0.2445 1952 5.049 %5
Rwork0.1938 36711 --
all0.196 ---
obs-38663 55.712 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 33.964 Å2
Baniso -1Baniso -2Baniso -3
1--0.109 Å2-0 Å20 Å2
2---0.221 Å20 Å2
3---0.33 Å2
Refinement stepCycle: LAST / Resolution: 1.9→99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4996 0 39 326 5361
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0125146
X-RAY DIFFRACTIONr_bond_other_d0.0450.0164507
X-RAY DIFFRACTIONr_angle_refined_deg1.6491.756963
X-RAY DIFFRACTIONr_angle_other_deg1.061.67810579
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5635595
X-RAY DIFFRACTIONr_dihedral_angle_2_deg12.3021028
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.41310821
X-RAY DIFFRACTIONr_dihedral_angle_6_deg14.61610213
X-RAY DIFFRACTIONr_chiral_restr0.0750.2776
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.025862
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021058
X-RAY DIFFRACTIONr_nbd_refined0.2240.21353
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1980.24408
X-RAY DIFFRACTIONr_nbtor_refined0.1830.22592
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0820.22758
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.4230.2264
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1740.217
X-RAY DIFFRACTIONr_nbd_other0.240.255
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2450.29
X-RAY DIFFRACTIONr_mcbond_it3.3443.5242366
X-RAY DIFFRACTIONr_mcbond_other3.3393.5242366
X-RAY DIFFRACTIONr_mcangle_it5.0475.2792956
X-RAY DIFFRACTIONr_mcangle_other5.0465.2792957
X-RAY DIFFRACTIONr_scbond_it4.2183.9432780
X-RAY DIFFRACTIONr_scbond_other4.1583.9112753
X-RAY DIFFRACTIONr_scangle_it6.485.7734003
X-RAY DIFFRACTIONr_scangle_other6.4245.7173962
X-RAY DIFFRACTIONr_lrange_it8.73149.5156022
X-RAY DIFFRACTIONr_lrange_other8.70949.1695977
X-RAY DIFFRACTIONr_ncsr_local_group_10.0840.056203
X-RAY DIFFRACTIONr_ncsr_local_group_20.0820.056271
X-RAY DIFFRACTIONr_ncsr_local_group_30.0770.056269
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)Weight position
11AX-RAY DIFFRACTIONLocal ncs0.084390.05009
12AX-RAY DIFFRACTIONLocal ncs0.084390.05009
23AX-RAY DIFFRACTIONLocal ncs0.081520.05009
24AX-RAY DIFFRACTIONLocal ncs0.081520.05009
35AX-RAY DIFFRACTIONLocal ncs0.07710.05009
36AX-RAY DIFFRACTIONLocal ncs0.07710.05009
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.9490.38310.31338X-RAY DIFFRACTION0.7703
1.949-2.0031.08210.308145X-RAY DIFFRACTION2.9282
2.003-2.0610.4110.324256X-RAY DIFFRACTION5.5905
2.061-2.1240.275190.307447X-RAY DIFFRACTION9.9637
2.124-2.1940.284680.2771017X-RAY DIFFRACTION23.9303
2.194-2.2710.368680.2721446X-RAY DIFFRACTION34.3622
2.271-2.3560.296950.2521770X-RAY DIFFRACTION43.9651
2.356-2.4530.3231050.2492200X-RAY DIFFRACTION56.7175
2.453-2.5620.2841250.2482763X-RAY DIFFRACTION73.151
2.562-2.6870.3291700.2383018X-RAY DIFFRACTION84.8549
2.687-2.8320.3261870.2333367X-RAY DIFFRACTION99.08
2.832-3.0030.2642080.2223173X-RAY DIFFRACTION99.9704
3.003-3.210.2381650.2073036X-RAY DIFFRACTION99.9064
3.21-3.4670.2411480.192841X-RAY DIFFRACTION99.9666
3.467-3.7980.2151370.1742628X-RAY DIFFRACTION100
3.798-4.2450.1961380.1512377X-RAY DIFFRACTION100
4.245-4.9010.1921030.1352107X-RAY DIFFRACTION99.9548
4.901-5.9980.214950.1781800X-RAY DIFFRACTION99.8946
5.998-8.4670.253530.1721451X-RAY DIFFRACTION99.8672
8.467-990.207550.18831X-RAY DIFFRACTION99.7748

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