title: Synthetic mimetics of the gp130 binding site for viral interleukin-6 as inhibitors of the vIL-6-gp130 interaction.
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.
authors: Helmholtz Centre for Infection Research, 38124 Braunschweig, GermanyInstitut Pasteur de Montevideo, CP 11400 Montevideo, UruguayFaculty of Life Sciences, Michael Smith Building, University of Manchester, Manchester M13 9PT, UKInstitute of Biochemistry, Christian Albrecht University Kiel, 24098 Kiel, Germany.
authors: Enge
authors: E
authors: Sudarman
authors: Helmholtz Centre for Infection Research, 38124 Braunschweig, GermanyInstitut Pasteur de Montevideo, CP 11400 Montevideo, UruguayFaculty of Life Sciences, Michael Smith Building, University of Manchester, Manchester M13 9PT, UKInstitute of Biochemistry, Christian Albrecht University Kiel, 24098 Kiel, Germany.
authors: Mariela
authors: M
authors: Bollati-Fogolín
authors: Helmholtz Centre for Infection Research, 38124 Braunschweig, GermanyInstitut Pasteur de Montevideo, CP 11400 Montevideo, UruguayFaculty of Life Sciences, Michael Smith Building, University of Manchester, Manchester M13 9PT, UKInstitute of Biochemistry, Christian Albrecht University Kiel, 24098 Kiel, Germany.
authors: Martin
authors: M
authors: Hafner
authors: Helmholtz Centre for Infection Research, 38124 Braunschweig, GermanyInstitut Pasteur de Montevideo, CP 11400 Montevideo, UruguayFaculty of Life Sciences, Michael Smith Building, University of Manchester, Manchester M13 9PT, UKInstitute of Biochemistry, Christian Albrecht University Kiel, 24098 Kiel, Germany.
authors: Werner
authors: W
authors: Müller
authors: Helmholtz Centre for Infection Research, 38124 Braunschweig, GermanyInstitut Pasteur de Montevideo, CP 11400 Montevideo, UruguayFaculty of Life Sciences, Michael Smith Building, University of Manchester, Manchester M13 9PT, UKInstitute of Biochemistry, Christian Albrecht University Kiel, 24098 Kiel, Germany.
authors: Jürgen
authors: J
authors: Scheller
authors: Helmholtz Centre for Infection Research, 38124 Braunschweig, GermanyInstitut Pasteur de Montevideo, CP 11400 Montevideo, UruguayFaculty of Life Sciences, Michael Smith Building, University of Manchester, Manchester M13 9PT, UKInstitute of Biochemistry, Christian Albrecht University Kiel, 24098 Kiel, Germany.
authors: Stefan
authors: S
authors: Rose-John
authors: Helmholtz Centre for Infection Research, 38124 Braunschweig, GermanyInstitut Pasteur de Montevideo, CP 11400 Montevideo, UruguayFaculty of Life Sciences, Michael Smith Building, University of Manchester, Manchester M13 9PT, UKInstitute of Biochemistry, Christian Albrecht University Kiel, 24098 Kiel, Germany.
authors: Jutta
authors: J
authors: Eichler
mesh_terms: D001665:Binding Sites; D050822:Cytokine Receptor gp130 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D019288:Herpesvirus 8, Human; D006801:Humans; D015850:Interleukin-6 / Q000737:chemistry* / Q000378:metabolism; D018716:Molecular Mimicry; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011991:Receptors, Virus / Q000037:antagonists & inhibitors / Q000737:chemistry; D014764:Viral Proteins / Q000737:chemistry* / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
chemical_list: D050822:Cytokine Receptor gp130; D015850:Interleukin-6; D010455:Peptides; D011991:Receptors, Virus; D014764:Viral Proteins; D000093242:Interleukin-6 Inhibitors