Xt. Zhu et al., STRUCTURAL STUDIES OF THE BINDING OF THE ANTIULCER DRUG SUCROSE OCTASULFATE TO ACIDIC FIBROBLAST GROWTH-FACTOR, Structure, 1(1), 1993, pp. 27-34
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.