Synthetic mimetics of the gp130 binding site for viral interleukin-6 as inhibitors of the vIL-6-gp130 interaction.
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.
Sudarman
Enge
E
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.
Bollati-Fogolín
Mariela
M
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.
Hafner
Martin
M
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.
Müller
Werner
W
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.
Scheller
Jürgen
J
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.
Rose-John
Stefan
S
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.
Eichler
Jutta
J
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.
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
D050822:Cytokine Receptor gp130; D015850:Interleukin-6; D010455:Peptides; D011991:Receptors, Virus; D014764:Viral Proteins; D000093242:Interleukin-6 Inhibitors