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

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 A 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.

Pubmed ID: 9808045

Authors

  • Livnah O
  • Johnson DL
  • Stura EA
  • Farrell FX
  • Barbone FP
  • You Y
  • Liu KD
  • Goldsmith MA
  • He W
  • Krause CD
  • Pestka S
  • Jolliffe LK
  • Wilson IA

Journal

Nature structural biology

Publication Data

November 19, 1998

Associated Grants

None

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Conserved Sequence
  • Crystallography, X-Ray
  • DNA-Binding Proteins
  • Dimerization
  • Erythropoietin
  • Humans
  • Mice
  • Milk Proteins
  • Models, Molecular
  • Molecular Sequence Data
  • Peptides, Cyclic
  • Phosphorylation
  • Protein Conformation
  • Receptors, Erythropoietin
  • Recombinant Fusion Proteins
  • STAT5 Transcription Factor
  • Signal Transduction
  • Trans-Activators
  • Tryptophan
  • Tyrosine