5MR4

Ligand-receptor complex.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.196 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Structure and biophysical characterization of the human full-length neurturin-GFRa2 complex: A role for heparan sulfate in signaling.

Sandmark, J.Dahl, G.Oster, L.Xu, B.Johansson, P.Akerud, T.Aagaard, A.Davidsson, P.Bigalke, J.M.Winzell, M.S.Rainey, G.J.Roth, R.G.

(2018) J Biol Chem 293: 5492-5508

  • DOI: https://doi.org/10.1074/jbc.RA117.000820
  • Primary Citation of Related Structures:  
    5MR4, 5MR5, 5NMZ

  • PubMed Abstract: 

    Neurturin (NRTN) provides trophic support to neurons and is considered a therapeutic agent for neurodegenerative diseases, such as Parkinson's disease. It binds to its co-receptor GFRa2, and the resulting NRTN-GFRa2 complex activates the transmembrane receptors rearranged during transfection (RET) or the neural cell adhesion molecule (NCAM). We report the crystal structure of NRTN, alone and in complex with GFRa2. This is the first crystal structure of a GFRa with all three domains and shows that domain 1 does not interact directly with NRTN, but it may support an interaction with RET and/or NCAM, via a highly conserved surface. In addition, biophysical results show that the relative concentration of GFRa2 on cell surfaces can affect the functional affinity of NRTN through avidity effects. We have identified a heparan sulfate-binding site on NRTN and a putative binding site in GFRa2, suggesting that heparan sulfate has a role in the assembly of the signaling complex. We further show that mutant NRTN with reduced affinity for heparan sulfate may provide a route forward for delivery of NRTN with increased exposure in preclinical in vivo models and ultimately to Parkinson's patients.


  • Organizational Affiliation

    From the Departments of Structure, Biophysics and Fragment-based Lead Generation, Discovery Sciences.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Neurturin
A, B
102Homo sapiensMutation(s): 0 
Gene Names: NRTN
UniProt & NIH Common Fund Data Resources
Find proteins for Q99748 (Homo sapiens)
Explore Q99748 
Go to UniProtKB:  Q99748
PHAROS:  Q99748
GTEx:  ENSG00000171119 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ99748
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
GDNF family receptor alpha-2
C, D
458Homo sapiensMutation(s): 0 
Gene Names: GFRA2GDNFRBRETL2TRNR2
UniProt & NIH Common Fund Data Resources
Find proteins for O00451 (Homo sapiens)
Explore O00451 
Go to UniProtKB:  O00451
PHAROS:  O00451
GTEx:  ENSG00000168546 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO00451
Sequence Annotations
Expand
  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.196 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 77.81α = 90
b = 125.811β = 101.93
c = 82.722γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-01-17
    Type: Initial release
  • Version 1.1: 2018-02-14
    Changes: Database references
  • Version 1.2: 2018-02-21
    Changes: Database references
  • Version 1.3: 2018-04-25
    Changes: Data collection, Database references
  • Version 1.4: 2024-01-17
    Changes: Data collection, Database references, Refinement description