PDBsum entry: 1axm

Growth factor

PDB-id: 1axm

Main view

Contents

Description

Header details

Header records

References

PROCHECK

Protein chains

130 a.a. *

Ligands

SGN-IDS-SGN-IDS-SGN ×2

IDS-SGN-IDS-SGN-IDS

Waters ×71

* Residue conservation analysis

Tools

Clefts Calculation

Bottom view	Right view

PDB id:

1axm

Name:

Growth factor

Title:

Heparin-linked biologically-active dimer of fibroblast growth factor

Structure:

Acidic fibroblast growth factor. Chain: a, b, c, d, e, f. Synonym: fgf-1. Engineered: yes. Other_details: for each of the decasaccharide chains in the asymmetric unit, five monosaccharide units are disordered

Source:

Homo sapiens. Human. Organism_taxid: 9606. Cell_line: jm109 de3. Organ: brain stem. Tissue: nerve. Cell: endothelial. Cellular_location: extracellular matrix. Gene: ecgf.

UniProt:

Chains A, B, C, D, E, F: P05230 (FGF1_HUMAN)

Seq:

155 a.a.

Struc:

130 a.a.

Key:	PfamA domain
Secondary structure	CATH domain

Resolution:

3.00Å

R-factor:

0.217

R-free:

0.304

Authors:

A.D.Digabriele,I.Lax,D.I.Chen,C.M.Svahn,M.Jaye, J.Schlessinger,W.A.Hendrickson

Key ref:

A.D.DiGabriele et al. (1998). Structure of a heparin-linked biologically active dimer of fibroblast growth factor.. Nature, 393, 812-817. [PubMed id: 9655399] [DOI: 10.1038/31741]

Date:

16-Oct-97

Release date:

22-Apr-98

Quick_links

Procheck

Surface

Key reference

DOI no: 10.1038/31741

Nature 393:812-817 (1998)

PubMed id: 9655399

Structure of a heparin-linked biologically active dimer of fibroblast growth factor.

A.D.DiGabriele, I.Lax, D.I.Chen, C.M.Svahn, M.Jaye, J.Schlessinger, W.A.Hendrickson.

ABSTRACT

The fibroblast growth factors (FGFs) form a large family of structurally related, multifunctional proteins that regulate various biological responses. They mediate cellular functions by binding to transmembrane FGF receptors, which are protein tyrosine kinases. FGF receptors are activated by oligomerization, and both this activation and FGF-stimulated biological responses require heparin-like molecules as well as FGF. Heparins are linear anionic polysaccharide chains; they are typically heterogeneously sulphated on alternating L-iduronic and D-glucosamino sugars, and are nearly ubiquitous in animal tissues as heparan sulphate proteoglycans on cell surfaces and in the extracellular matrix. Although several crystal structures have been described for FGF molecules in complexes with heparin-like sugars, the nature of a biologically active complex has been unknown until now. Here we describe the X-ray crystal structure, at 2.9 A resolution, of a biologically active dimer of human acidic FGF in a complex with a fully sulphated, homogeneous heparin decassacharide. The dimerization of heparin-linked acidic FGF observed here is an elegant mechanism for the modulation of signalling through combinatorial homodimerization and heterodimerization of the 12 known members of the FGF family.

Selected figure(s)

Figure 2.
Figure 2 Structures of heparin-linked aFGF dimers. a, This sigma-weighted electron-density map at 2.9 Å resolution in the region of the bound heparin was generated without the decasaccharide in the model. Blue contour is at 1 and pink contour is at 4 . b, A stereo view of heparin-linked dimer A (orthorhombic asymmetric unit) of human aFGF. The amino and carboxy termini of the protomers, and the O1 and O4 ends of the sugar, are labelled. The location of the alpha carbon atom of every tenth residue is shown by a numbered black circle. c, The superposition of one aFGF protomer (A1, B3 and C5) (bottom) from each aFGF dimer in the orthorhombic asymmetric unit, using program O (ref. 26), shows the variabiity in positions of the second protomers (A2, blue, B4, cyan, C6, yellow worms; top) and heparin chains (A[sugar], blue, B[sugar], cyan, C[sugar], yellow; centre). Protomer A1 is depicted as a blue ribbon (bottom) showing labelled secondary structure^27. The hexagonal asymmetric unit (H7, H8 and H[sugar] are not shown) is most similar to aFGF dimer A. Rotations and translations that superimpose the second protomers B4, H8 and C6 on A2 are, respectively, 16.2° and 0.6 Å, 7.5° and 0.4 Å, and 16.8° and 1.5 Å. Prepared with program O (a) and SETOR28 (b, c).

Figure 3.
Figure 3 a-d, Details of hydrogen bonding between aFGF protomers (ribbons) and heparin (ball-and-stick diagrams) in aFGF dimers. A and C. After C superposition, protomers of one dimer and bound sugar were placed side by side for comparison. A1 (a) and C5 (c) bind A[sugar] and C[sugar], respectively, with 'O1 to O4' polarity. A2 (b) and C6 (d) bind the corresponding sugars with 'O4 to O1' polarity. All side chains within 4 Å of the sugar are shown. Atoms are colour-coded by element (C, white; O, red; S, yellow; N, blue) and interactions are shown as dashed yellow lines. Monosaccharide units are labelled as S for N-acetyl glucosamine and I for iduronic acid. e, Superposition of the six aFGF protomers and bound heparin chains in the orthorhombic asymmetric unit looking down on the sugar-binding loop (blue worm segment). Protein side chains and corresponding sulphate groups (spheres) are a different colour for each protomer. Three major sulphate-group binding sites and the amino-acid side chains that form these sites are shown. f, Electrostatic potential mapped onto the molecular surface of an aFGF protomer orientated as in e. A large patch of positive electrostatic potential (blue represents +10 e per Å) distinguishes the heparin-binding site (heparin is shown in yellow). g, Surface representation of aFGF dimer A (Fig. 2b) rotated by 90° about two perpendicular axes. Yellow surfaces represent FGFR-binding sites. A two-fold axis runs vertically in the plane of the page between the protomers, such that the yellow surface at the front of the blue protomer is at the back of the purple protomer. h, A model for FGFR dimerization by binding of the extracellular (numbered) FGFR domains (cyan) to the heparin (orange zigzag)-linked aFGF dimer (blue and purple circles), orientated as in g. Prepared with SETOR (a-d, e, g)28 and GRASP (f)29.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (1998, 393, 812-817) copyright 1998.

Figures were selected by the author.