PDBsum entry: 1hkn

Growth factor

PDB id: 1hkn

Contents

Protein chains

(+ 0 more) 129 a.a. *

Ligands

N2M ×2

Waters ×103

* Residue conservation analysis

PDB id:

1hkn

Name:

Growth factor

Title:

A complex between acidic fibroblast growth factor and 5-amino-2-naphthalenesulfonate

Structure:

Heparin-binding growth factor 1. Chain: a, b, c, d, e, f. Synonym: hbgf-1, acidic fibroblast growth factor, afgf, beta-endothelial cell growth factor, ecgf- beta. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.00Å R-factor: 0.228 R-free: 0.259

Authors:

C.Fernandez-Tornero,R.M.Lozano,G.Gimenez-Gallego,A.Romero

Key ref:

C.Fernández-Tornero et al. (2003). Leads for development of new naphthalenesulfonate derivatives with enhanced antiangiogenic activity: crystal structure of acidic fibroblast growth factor in complex with 5-amino-2-naphthalene sulfonate. J Biol Chem, 278, 21774-21781. PubMed id: 12676958 DOI: 10.1074/jbc.M212833200

Date:

10-Mar-03 Release date: 11-Mar-04

Protein chains

P05230  (FGF1_HUMAN) -  Heparin-binding growth factor 1

Seq: 155 a.a.

Struc: 129 a.a.

 Gene Ontology (GO) functional annotation 

• Cellular component: extracellular region (8 terms)
• Biological process: multicellular organismal development (22 terms)
• Biochemical function: protein binding (6 terms)

DOI no: 10.1074/jbc.M212833200

J Biol Chem 278:21774-21781 (2003)

PubMed id: 12676958

Leads for development of new naphthalenesulfonate derivatives with enhanced antiangiogenic activity: crystal structure of acidic fibroblast growth factor in complex with 5-amino-2-naphthalene sulfonate.

C.Fernández-Tornero, R.M.Lozano, M.Redondo-Horcajo, A.M.Gómez, J.C.López, E.Quesada, C.Uriel, S.Valverde, P.Cuevas, A.Romero, G.Giménez-Gallego.

ABSTRACT

Inhibition of angiogenesis-promoting factors such as fibroblast growth factors is considered to be a potential procedure for inhibiting solid tumor growth. Although several peptide-based inhibitors are currently under study, the development of antiangiogenic compounds of small molecular size is a pharmacological goal of considerable interest. We have already shown that certain naphthalene sulfonates constitute minimal functional substitutes of the antiangiogenic compounds of the suramin and suradista family. Using those data as a lead, we have carried out a rational search for new angiogenesis inhibitors that could provide new pharmacological insights for the development of antiangiogenic treatments. The results of the study strongly underline the relevance of the stereochemistry for an efficient inhibition of acidic fibroblast growth factor mitogenic activity by the naphthalene sulfonate family and allow us to formulate rules to aid in searching for new inhibitors and pharmaceutical developments. To provide further leads for such developments and acquire a detailed insight into the basis of the inhibitory activity of the naphthalene sulfonate derivatives, we solved the three-dimensional structure of acidic fibroblast growth factor complexed to 5-amino-2-naphthalenesulfonate, the most pharmacologically promising of the identified inhibitors. The structure shows that binding of this compound would hamper the interaction of acidic fibroblast growth factor with the different components of the cell membrane mitogenesis-triggering complex.

Selected figure(s)

Figure 4.
FIG. 4. 5-Amino-2-NMS is anchored to the heparin-binding site of aFGF. a, stereoview of the three-dimensional structure of aFGF backbone inscribed into its molecular surface bound to 5-amino-2-NMS. Acidic and basic amino acid residues at the surface are shown in red and blue, respectively. 5-Amino-2-NMS is represented using ball-and-stick models, with carbon, nitrogen, oxygen, and sulfur atoms colored black, blue, red, and green, respectively. The side chains of the most important heparin-binding residues (41, 45) are in a ball-and-stick representation and labeled. b, molecular surface representation of aFGF in complex with 5-amino-2-NMS, shown as in a with the heparin molecule (yellow) modeled by superposition with the aFGF according to DiGabriele et al. (41). c, stereoview of the backbone of aFGF bound to 5-amino-2-NMS with the side chains of the main residues that interact with either heparin (see panel a) or 5-amino-2-NMS represented in ball-and-sticks (labeled those that establish hydrogen bonds with 5-amino-2-NMS). The hydrogen bonds are shown as dashed lines in cyan. The figure has been created using GRASP (53), MOLSCRIPT (54), and Raster3D (55).

Figure 5.
FIG. 5. Effects of 5-amino-2-NMS binding on the structure of aFGF. a, molecular surface representation of aFGF in complex with heparin according to DiGabriele et al. (41). b, molecular surface representation of aFGF in complex with 5-amino-2-NMS. The ligands are shown as ball-and-stick models, with carbon, nitrogen, oxygen, and sulfur atoms colored black, blue, red, and yellow, respectively. Acidic and basic amino acid residues at the surface are shown in red and blue, respectively. c, stereoview of the superposition of the C traces of aFGF bound to heparin (cyan; heparin not represented) and bound to 5-amino-2-NMS (yellow). The main difference is observed at the 8/ 9 loop (arrow).

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 21774-21781) copyright 2003.

Figures were selected by an automated process.