alexa Binding of madindoline A to the extracellular domain of gp130.

Author(s): Saleh AZ, Greenman KL, Billings S, Van Vranken DL, Krolewski JJ

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Abstract Elevated levels of IL-6 and IL-11 are associated with multiple myeloma, rheumatoid arthritis, hypercalcemia, cancer cachexia, and Castleman's disease. Madindoline A (MadA), isolated from Streptomyces nitrosporeus K93-0711, specifically inhibits the growth of IL-6- and IL-11-dependent cell lines, most likely by interfering with the homodimerization of gp130. This raises the possibility that MadA can be used as a model compound for the development of novel chemotherapeutic agents. In this report, we demonstrate that the binding of MadA to gp130 is specific and noncovalent, and displays a relatively low affinity. Furthermore, we show that the tricyclic 3a-hydroxytetrahydrofuro[2,3-b]indole (HFI) moiety of MadA alone is not sufficient for binding. Matrix-bound MadA precipitates a protein composed of the extracellular domain of gp130 fused to the Fc region of the immunoglobulin heavy chain. Binding is inhibited in a dose-dependent manner by preincubation with free MadA. The K(D) for binding of MadA to gp130 is 288 microM, as determined by surface plasmon resonance (SPR)-based biosensor analysis. The HFI portion of MadA does not bind to gp130 in either affinity precipitation or SPR analyses. Finally, MadA, but not the HFI portion, inhibits IL-6-dependent Stat3 tyrosine phosphorylation in HepG2 cells. This article was published in Biochemistry and referenced in

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