PDBsum entry 1iil

Growth factor/growth factor receptor

PDB id: 1iil

Contents

Protein chains

134 a.a. *

200 a.a. *

215 a.a. *

Waters ×77

* Residue conservation analysis

PDB id:

1iil

Name:

Growth factor/growth factor receptor

Title:

Crystal structure of pro253arg apert mutant fgf receptor 2 (fgfr2) in complex with fgf2

Structure:

Heparin-binding growth factor 2. Chain: a, b, c, d. Synonym: fgf2, hbgf-2, basic fibroblast growth factor, bfgf. Engineered: yes. Mutation: yes. Fibroblast growth factor receptor 2. Chain: e, f, g, h. Fragment: extracellular ligand binding domain consisting of ig-like domains ii (d2) and iii (d3), residues 147-366.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Biol. unit:

Dimer (from PQS)

Resolution:

2.30Å R-factor: 0.237 R-free: 0.259

Authors:

O.A.Ibrahimi,A.V.Eliseenkova,A.N.Plotnikov,D.M.Ornitz,M.Mohammadi

Key ref:

O.A.Ibrahimi et al. (2001). Structural basis for fibroblast growth factor receptor 2 activation in Apert syndrome. Proc Natl Acad Sci U S A, 98, 7182-7187. PubMed id: 11390973 DOI: 10.1073/pnas.121183798

Date:

23-Apr-01 Release date: 09-May-01

Protein chains

P09038  (FGF2_HUMAN) -  Fibroblast growth factor 2 from Homo sapiens

Seq: 288 a.a.

Struc: 134 a.a.*

Protein chains

P21802  (FGFR2_HUMAN) -  Fibroblast growth factor receptor 2 from Homo sapiens

Seq: 821 a.a.

Struc: 200 a.a.*

Protein chains

P21802  (FGFR2_HUMAN) -  Fibroblast growth factor receptor 2 from Homo sapiens

Seq: 821 a.a.

Struc: 215 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains E, F, G, H: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1073/pnas.121183798

Proc Natl Acad Sci U S A 98:7182-7187 (2001)

PubMed id: 11390973

Structural basis for fibroblast growth factor receptor 2 activation in Apert syndrome.

O.A.Ibrahimi, A.V.Eliseenkova, A.N.Plotnikov, K.Yu, D.M.Ornitz, M.Mohammadi.

ABSTRACT

Apert syndrome (AS) is characterized by craniosynostosis (premature fusion of cranial sutures) and severe syndactyly of the hands and feet. Two activating mutations, Ser-252 --> Trp and Pro-253 --> Arg, in fibroblast growth factor receptor 2 (FGFR2) account for nearly all known cases of AS. To elucidate the mechanism by which these substitutions cause AS, we determined the crystal structures of these two FGFR2 mutants in complex with fibroblast growth factor 2 (FGF2). These structures demonstrate that both mutations introduce additional interactions between FGFR2 and FGF2, thereby augmenting FGFR2-FGF2 affinity. Moreover, based on these structures and sequence alignment of the FGF family, we propose that the Pro-253 --> Arg mutation will indiscriminately increase the affinity of FGFR2 toward any FGF. In contrast, the Ser-252 --> Trp mutation will selectively enhance the affinity of FGFR2 toward a limited subset of FGFs. These predictions are consistent with previous biochemical data describing the effects of AS mutations on FGF binding. Alterations in FGFR2 ligand affinity and specificity may allow inappropriate autocrine or paracrine activation of FGFR2. Furthermore, the distinct gain-of-function interactions observed in each crystal structure provide a model to explain the phenotypic variability among AS patients.

Selected figure(s)

Figure 1.
Fig. 1. AS mutations do not affect the relative disposition of D2 and D3 in FGFR2. C traces of wild-type (green), mutant Ser252Trp (blue), and Pro253Arg (red) FGFR2s are superimposed. The N and C termini are denoted by the letters NT and CT. This figure was made by using programs MOLSCRIPT (23) and RASTER3D (24). The C traces of Ser252Trp and Pro253Arg mutant FGFR2s deviate by only 0.39 Å and 0.31 Å, respectively, from the C trace of wild-type FGFR2.

Figure 2.
Fig. 2. Gain-of-function interactions between the AS mutant FGFR2s and FGF2. (A) Additional contacts between the N terminus of FGF2 and the Ser252Trp mutant FGFR2. (B) Hydrogen bonds between FGF2 and Arg-253 of the Pro253Arg mutant FGFR2. D2 and D3 of FGFR2 are shown in green and cyan, respectively. The short linker that connects D2 and D3 is colored gray. FGF2 is shown in orange. In addition, the FGF2 N-terminal region (Phe^21-Pro-Pro-Gly24), which is ordered only in the Ser252Trp mutant FGFR2-FGF2 structure, is colored purple. Oxygen atoms are red, nitrogen atoms blue, and carbon atoms have the same coloring as the molecules to which they belong. Dotted lines represent hydrogen bonds. The hydrogen-bonding distances are indicated. (Right) Views of whole structure in the exact orientation as in the detailed views are shown, and the region of interest is boxed. This figure was created by using the programs MOLSCRIPT and RASTER3D.

Figures were selected by an automated process.