STRUCTURAL STUDIES OF THE BINDING OF THE ANTIULCER DRUG SUCROSE OCTASULFATE TO ACIDIC FIBROBLAST GROWTH-FACTOR

Background: The anti-ulcer drug sucrose octasulfate (SOS) binds to fib roblast growth factors (FGFs), proteins which stimulate the growth and differentiation of several cell types, including stomach epithelial c ells. It is believed that SOS stabilizes FGFs against acid denaturatio n in the stomach, thus enhancing their ability to stimulate healing of ulcerated tissue. SOS binds to the same site on FGF as heparin and ot her proteoglycans; in vivo, FGF must bind to cell-surface proteoglycan s or to heparin before it can interact with FGF receptors and stimulat e growth. The details of this process are not understood. Results: We report the crystal structure of a 1:1 complex between acidic FGF (aFGF ) and SOS at 2.7 Angstrom resolution. SOS binds to a positively charge d region of aFGF, largely composed of residues 112-127, and makes cont acts primarily with Lys112, Arg116, Lys118, and Arg122. This region is also important in binding heparin. The overall conformation of aFGF i s not changed by binding SOS, although the positions of some side chai ns in the binding site shift by as much as 6 Angstrom. Conclusion: The SOS-FGF crystal structure is consistent with the model that SOS stabi lizes FGF by neutralizing several positively charged residues that wou ld destabilize the native structure by electrostatic repulsion. On the basis of this structure, we provide a model for the complex of hepari n with an FGF dimer. Such inter actions may facilitate FGF receptor di merization, which may be important in receptor signaling.