An antagonist peptide-EPO receptor complex suggests that receptor dimerization is not sufficient for activation

Oded Livnah, Dana L. Johnson, Enrico A. Stura, Francis X. Farrel, Francis P. Barbone, Yun You, Kathleen D. Liu, Mark A. Goldsmith, Wen He, Christopher D. Krause, Sidney Pestka, Linda K. Jolliffe*, Ian A. Wilson

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

193 Scopus citations

Abstract

Dimerization of the erythropoietin (EPO) receptor (EPOR), in the presence of either natural (EPO) or synthetic (EPO-mimetic peptides, EMPs) ligands is the principal extracellular event that leads to receptor activation. The crystal structure of the extracellular domain of EPOR bound to an inactive (antagonist) peptide at 2.7 Å resolution has unexpectedly revealed that dimerization still occurs, but the orientation between receptor molecules is altered relative to active (agonist) peptide complexes. Comparison of the biological properties of agonist and antagonist EMPs with EPO suggests that the extracellular domain orientation is tightly coupled to the cytoplasmic signaling events and, hence, provides valuable new insights into the design of synthetic ligands for EPOR and other cytokine receptors.

Original languageAmerican English
Pages (from-to)993-1004
Number of pages12
JournalNature Structural Biology
Volume5
Issue number11
DOIs
StatePublished - Nov 1998

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