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

doi:10.1038/2965

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

Department of Biological Chemistry

Research output: Contribution to journal › Article › peer-review

195 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 language	English
Pages (from-to)	993-1004
Number of pages	12
Journal	Nature Structural Biology
Volume	5
Issue number	11
DOIs	https://doi.org/10.1038/2965
State	Published - Nov 1998

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Livnah, O., Johnson, D. L., Stura, E. A., Farrel, F. X., Barbone, F. P., You, Y., Liu, K. D., Goldsmith, M. A., He, W., Krause, C. D., Pestka, S., Jolliffe, L. K., & Wilson, I. A. (1998). An antagonist peptide-EPO receptor complex suggests that receptor dimerization is not sufficient for activation. Nature Structural Biology, 5(11), 993-1004. https://doi.org/10.1038/2965

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title = "An antagonist peptide-EPO receptor complex suggests that receptor dimerization is not sufficient for activation",

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 {\AA} 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.",

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

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AU - Barbone, Francis P.

AU - You, Yun

AU - Liu, Kathleen D.

AU - Goldsmith, Mark A.

AU - He, Wen

AU - Krause, Christopher D.

AU - Pestka, Sidney

AU - Jolliffe, Linda K.

AU - Wilson, Ian A.

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AB - 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.

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

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