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Structural studies of the binding of the anti-ulcer drug sucrose octasulfate to acidic fibroblast growth factor

Zhu, Xiaotian and Hsu, Barbara T. and Rees, Douglas C. (1993) Structural studies of the binding of the anti-ulcer drug sucrose octasulfate to acidic fibroblast growth factor. Structure, 1 (1). pp. 27-34. ISSN 0969-2126.

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Background: The anti-ulcer drug sucrose octasulfate (SOS) binds to fibroblast growth factors (FGFs), proteins which stimulate the growth and differentiation of several cell types, including stomach epithelial cells. It is believed that SOS stabilizes FGFs against acid denaturation in the stomach, thus enhancing their ability to stimulate healing of ulcerated tissue. SOS binds to the same site on FGF as heparin and other proteoglycans, in vivo, FGF must bind to cell-surface proteoglycans or to heparin before it can interact with FGF receptors and stimulate 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 Å resolution. SOS binds to a positively charged region of aFGF, largely composed of residues 112–127, and makes contacts primarily with Lys112, Arg116, Lys118, and Arg122. This region is also important in binding heparin. The overall conformation of aFGF is not changed by binding SOS, although the positions of some side chains in the binding site shift by as much as 6 Å. Conclusion: The SOS-FGF crystal structure is consistent with the model that SOS stabilizes FGF by neutralizing several positively charged residues that would destabilize the native structure by electrostatic repulsion. On the basis of this structure, we provide a model for the complex of heparin with an FGF dimer. Such interactions may facilitate FGF receptor dimerization, which may be important in receptor signaling.

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Rees, Douglas C.0000-0003-4073-1185
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Additional Information:© 1993 Current Biology Ltd. Received: 24 May 1993; revised: 2 July 1993. Accepted: 8 July 1993. We thank AJ Chirino for his contributions to the graphics and refinement, T Arakawa and GM Fox of Amgen for providing aFGF, and D Bar-Shalom of Bukh Meditec for the SOS sample. This work was supported by in part by USPHS GM39558 and GM45162 (for the X-ray and computer facilities).
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Subject Keywords:anti-ulcer drugs, fibroblast growth factors, heparin, sucrose octasulfate
Issue or Number:1
Record Number:CaltechAUTHORS:20150205-141809743
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Official Citation:Xiaotian Zhu, Barbara T Hsu, Douglas C Rees, Structural studies of the binding of the anti-ulcer drug sucrose octasulfate to acidic fibroblast growth factor, Structure, Volume 1, Issue 1, 15 September 1993, Pages 27-34, ISSN 0969-2126, (
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ID Code:54453
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Deposited On:08 Feb 2015 02:41
Last Modified:03 Oct 2019 07:57

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