2FDB

Crystal Structure of Fibroblast growth factor (FGF)8b in complex with FGF Receptor (FGFR) 2c


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.28 Å
  • R-Value Free: 0.272 
  • R-Value Work: 0.239 
  • R-Value Observed: 0.239 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Structural basis by which alternative splicing modulates the organizer activity of FGF8 in the brain

Olsen, S.K.Li, J.Y.H.Bromleigh, C.Eliseenkova, A.V.Ibrahimi, O.A.Lao, Z.Zhang, F.Linhardt, R.J.Joyner, A.L.Mohammadi, M.

(2006) Genes Dev 20: 185-198

  • DOI: https://doi.org/10.1101/gad.1365406
  • Primary Citation of Related Structures:  
    2FDB

  • PubMed Abstract: 

    Two of the four human FGF8 splice isoforms, FGF8a and FGF8b, are expressed in the mid-hindbrain region during development. Although the only difference between these isoforms is the presence of an additional 11 amino acids at the N terminus of FGF8b, these isoforms possess remarkably different abilities to pattern the midbrain and anterior hindbrain. To reveal the structural basis by which alternative splicing modulates the organizing activity of FGF8, we solved the crystal structure of FGF8b in complex with the "c" splice isoform of FGF receptor 2 (FGFR2c). Using surface plasmon resonance (SPR), we also characterized the receptor-binding specificity of FGF8a and FGF8b, the "b" isoform of FGF17 (FGF17b), and FGF18. The FGF8b-FGFR2c structure shows that alternative splicing permits a single additional contact between phenylalanine 32 (F32) of FGF8b and a hydrophobic groove within Ig domain 3 of the receptor that is also present in FGFR1c, FGFR3c, and FGFR4. Consistent with the structure, mutation of F32 to alanine reduces the affinity of FGF8b toward all these receptors to levels characteristic of FGF8a. More importantly, analysis of the mid-hindbrain patterning ability of the FGF8b(F32A) mutant in chick embryos and murine midbrain explants shows that this mutation functionally converts FGF8b to FGF8a. Moreover, our data suggest that the intermediate receptor-binding affinities of FGF17b and FGF18, relative to FGF8a and FGF8b, also account for the distinct patterning abilities of these two ligands. We also show that the mode of FGF8 receptor-binding specificity is distinct from that of other FGFs and provide the first biochemical evidence for a physiological FGF8b-FGFR1c interaction during mid-hindbrain development. Consistent with the indispensable role of FGF8 in embryonic development, we show that the FGF8 mode of receptor binding appeared as early as in nematodes and has been preserved throughout evolution.


  • Organizational Affiliation

    Department of Pharmacology, New York University School of Medicine, New York, New York 10016, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
fibroblast growth factor 8 isoform BA [auth M],
C [auth N]
164Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P55075 (Homo sapiens)
Explore P55075 
Go to UniProtKB:  P55075
PHAROS:  P55075
GTEx:  ENSG00000107831 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP55075
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Fibroblast growth factor receptor 2B [auth P],
D [auth R]
220Homo sapiensMutation(s): 1 
Gene Names: FGFR2BEKKSAM
EC: 2.7.1.112
UniProt & NIH Common Fund Data Resources
Find proteins for P21802 (Homo sapiens)
Explore P21802 
Go to UniProtKB:  P21802
PHAROS:  P21802
GTEx:  ENSG00000066468 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP21802
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.28 Å
  • R-Value Free: 0.272 
  • R-Value Work: 0.239 
  • R-Value Observed: 0.239 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 170.846α = 90
b = 46.908β = 91.66
c = 109.616γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
SCALEPACKdata scaling
AMoREphasing
CNSrefinement
HKL-2000data reduction

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2006-02-07
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2021-10-20
    Changes: Database references
  • Version 1.4: 2023-08-30
    Changes: Data collection, Refinement description