PDBsum entry: 1nun

Hormone/growth factor/membrane protein

PDB-id: 1nun

Asymmetric unit

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Description

Header details

Header records

References

PROCHECK

Protein chains

139 a.a. *

209 a.a. *

Ligands

SO4 ×2

15P

Waters ×25

* Residue conservation analysis

Tools

Clefts Calculation

Biological unit*, tetramer
(*as deduced by PQS)

PDB id:

1nun

Name:

Hormone/growth factor/membrane protein

Title:

Crystal structure analysis of the fgf10-fgfr2b complex

Structure:

Fibroblast growth factor-10. Chain: a. Synonym: fgf-10, keratinocyte growth factor receptor, k- sam protein, protein tyrosine kinase, receptor like 14, fgf receptor, bacteria-expressed kinase, fibroblast growth factor receptor bek, tyrosylprotein kinase, hydroxyaryl- protein kinase. Engineered: yes. Fibroblast growth factor receptor 2 isoform 2.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: fgf10. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.

Biological unit:

Tetramer (from PQS)

UniProt:

Chain A: O15520 (FGF10_HUMAN)

Seq:	208 a.a.
Struc:	139 a.a.

Chain B: P21802 (FGFR2_HUMAN)

Seq:

Struc:

Seq:

Struc:

Seq:

Struc:

Seq:

821 a.a.

Struc:

209 a.a.*

Key:	PfamA domain	PfamB domain
Secondary structure	CATH domain

* PDB and UniProt seqs differ at 22 residue positions (black crosses)

Enzyme class:

Chain B: E.C.2.7.10.1   [IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Reaction:

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate

Resolution:

2.90Å

R-factor:

0.239

R-free:

0.288

Authors:

B.K.Yeh,M.Igarashi,A.V.Eliseenkova,A.N.Plotnikov,I.Sher, D.Ron,S.A.Aaronson,M.Mohammadi

Key ref:

B.K.Yeh et al. (2003). Structural basis by which alternative splicing confers specificity in fibroblast growth factor receptors.. Proc Natl Acad Sci U S A, 100, 2266-2271. [PubMed id: 12591959] [DOI: 10.1073/pnas.0436500100]

Date:

31-Jan-03

Release date:

11-Feb-03

Quick_links

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Clefts

Surface

Key reference

DOI no: 10.1073/pnas.0436500100

Proc Natl Acad Sci U S A 100:2266-2271 (2003)

PubMed id: 12591959

Structural basis by which alternative splicing confers specificity in fibroblast growth factor receptors.

B.K.Yeh, M.Igarashi, A.V.Eliseenkova, A.N.Plotnikov, I.Sher, D.Ron, S.A.Aaronson, M.Mohammadi.

ABSTRACT

Binding specificity between fibroblast growth factors (FGFs) and their receptors (FGFRs) is essential for mammalian development and is regulated primarily by two alternatively spliced exons, IIIb ("b") and IIIc ("c"), that encode the second half of Ig-like domain 3 (D3) of FGFRs. FGF7 and FGF10 activate only the b isoform of FGFR2 (FGFR2b). Here, we report the crystal structure of the ligand-binding portion of FGFR2b bound to FGF10. Unique contacts between divergent regions in FGF10 and two b-specific loops in D3 reveal the structural basis by which alternative splicing provides FGF10-FGFR2b specificity. Structure-based mutagenesis of FGF10 confirms the importance of the observed contacts for FGF10 biological activity. Interestingly, FGF10 binding induces a previously unobserved rotation of receptor Ig domain 2 (D2) to introduce specific contacts with FGF10. Hence, both D2 and D3 of FGFR2b contribute to the exceptional specificity between FGF10 and FGFR2b. We propose that ligand-induced conformational change in FGFRs may also play an important role in determining specificity for other FGF-FGFR complexes.

Selected figure(s)

Figure 5.
Fig. 5. FGF10-induced D2 rotation contributes to FGF10-FGFR2b specificity. (a) Relationship between the D2 domains after superimposition of FGF10 and FGF2 from the FGF10-FGFR2b and FGF2-FGFR2c structures. For the sake of clarity, D3 and the linker region are not shown. The direction and degree of rotation between the two domains is shown. D2 of FGFR2b is colored blue. D2 of FGFR2c is colored gray. The A' strands of both domains are shown as -strand arrows. The remainders of the domains are displayed as C coils. FGF10 is shown in orange. (b) Interactions at the FGF10-D2 interface. The side chains of interacting residues are displayed. (Right) A view of the FGF10-FGFR2b complex, with the region of interest indicated by a square. FGF10 and FGFR2b are colored as in Fig. 1. Oxygen atoms are colored red, nitrogen blue, and carbon atoms the same color as the molecules to which they belong.

Figure 6.
Fig. 6. Conformation of the FGFR2b linker region. (a) Interactions of the FGFR-invariant linker Arg-251 with FGF10. The side chains of interacting residues are displayed. (Right) A view of the whole FGF10-FGFR2b structure, with the region of interest indicated by a square. FGF10 and FGFR2b are colored as in Fig. 1. Oxygen atoms are colored red, nitrogen blue, and carbon atoms the same color as the molecules to which they belong. (b) Configuration of the FGFR-invariant linker Pro-253 in the FGF10-FGFR2b and FGF1-FGFR2c-heparin structures. The equivalent D2s from the FGF10-FGFR2b and FGF1-FGFR2c-heparin structures are superimposed (rmsd = 0.652 Å). FGFR2b is colored yellow, and FGFR2c is colored blue. The location of the linker prolines are indicated by arrows. Note the dramatic difference in the position of D3 between the two structures. (c) A FGF10-FGFR2b model with Pro-253 in the cis conformation. This model was generated by separately superimposing FGF10 and FGFR2b-D3 from the FGF10-FGFR2b structure onto FGF1 and FGFR2c-D3 in the FGF1-FGFR2c-heparin structure (rmsd = 0.791 Å and 0.668 Å, respectively). D2 and D3 are shown in green and blue, respectively. The alternatively spliced half of D3 is colored purple. FGF1 is displayed as a black C coil, and FGF10 is displayed as a thicker orange coil. FGF10 regions that interact with D3 in the FGF10-FGFR2b structure are colored red. In addition, FGF10 residues whose mutations reduce the ability of FGF10 to activate FGFR2b are rendered in ball-and-stick. The N and C termini of the receptor are labeled NT and CT, respectively.

Figures were selected by the author.