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

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作者
Oded Livnah
Dana L. Johnson
Enrico A. Stura
Francis X. Farrell
Francis P. Barbone
Yun You
Kathleen D. Liu
Mark A. Goldsmith
Wen He
Christopher D. Krause
Sidney Pestka
Linda K. Jolliffe
Ian A. Wilson
机构
[1] The Scripps Research Institute,Department of Molecular Biology and the Skaggs Institute for Chemical Biology
[2] R.W. Johnson Pharmaceutical Research Institute,Department of Medicine
[3] Drug Discovery Research,Department of Biological Chemistry
[4] Gladstone Institute of Virology and Immunology,undefined
[5] School of Medicine,undefined
[6] UCSF,undefined
[7] Robert Wood Johnson Medical School-UMDNJ,undefined
[8] Institute of Life Sciences,undefined
[9] The Wolfson Centre for Applied Structural Biology,undefined
[10] The Hebrew University of Jerusalem,undefined
[11] Departement d'Ingenierie et d'Etude des Proteines,undefined
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摘要
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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页码:993 / 1004
页数:11
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