AN ANTAGONIST PEPTIDE EPO RECEPTOR COMPLEX SUGGESTS THAT RECEPTOR DIMERIZATION IS NOT SUFFICIENT FOR ACTIVATION

Dimerization of the erythropoietin (EPO) receptor (EPOR), in the prese nce of either natural (EPO) or synthetic (EPO-mimetic peptides, EMPs) ligands is the principal extracellular event that leads to receptor ac tivation. The crystal structure of the extracellular domain of EPOR bo und to an inactive (antagonist) peptide at 2.7 Angstrom resolution has unexpectedly revealed that dimerization still occurs, but the orienta tion between receptor molecules is altered relative to active (agonist ) peptide complexes. Comparison of the biological properties of agonis t 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 l igands for EPOR and other cytokine receptors.