Synthetic Mimetics of the gp130 Binding Site for Viral Interleukin-6 as Inhibitors of the vIL-6–gp130 Interaction
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ABSTRACT:
The transmembrane protein gp130 acts as the
signal transducing receptor subunit for interleukin-
6 type cytokines, including viral interleukin-6,
which is encoded by the Kaposi’s sarcoma-associated
herpes virus. Viral interleukin-6 has been
shown to mimic human IL-6 functions, including
activation of the JAK1 and STAT1⁄ 3 signaling
pathways. Based on the crystal structure of three
extracellular domains of gp130 in complex with
viral interleukin-6, we have designed and synthesized
a range of assembled peptides that mimic
the sequentially discontinuous binding site of
gp130 for viral interleukin-6. These peptides,
which present the three binding site fragments
of gp130 in a nonlinear, discontinuous fashion,
were shown to inhibit the interaction of gp130
with viral interleukin-6, as well as the stimulation
of viral interleukin-6-induced cell proliferation.
These results validate the concept of synthetic
mimicry of discontinuous protein-binding sites
through assembled peptides, and the use of such
molecules as modulators of protein–ligand interactions.
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