FUNCTIONAL MIMICRY OF A PROTEIN HORMONE BY A PEPTIDE AGONIST - THE EPO RECEPTOR COMPLEX AT 2.8-ANGSTROM

The functional mimicry of a protein by an unrelated small molecule has been a formidable challenge. Now, however, th biological activity of a 166-residue hematopoietic growth hormone, erythropoietin (EPO), with is class 1 cytokine receptor has been mimicked by a 20-residue cyclic peptide unrelated in sequence to the natural ligand. The crystal stru cture at 2.8 Angstrom resolution of a complex of this agonist peptide with the extracellular domain of EPO receptor reveals that a peptide d imer induces an almost perfect twofold dimerization of the receptor. T he dimer assembly differs from that of the human growth hormone (hGH) receptor complex and suggests that more than one mode of dimerization may be able to indue signal transduction and cell proliferation. The E PO receptor binding site, defined by peptide interaction, corresponds to the smaller functional epitope identified for hGH receptor. Similar ly, the EPO mimetic peptide ligand can be considered as a minimal horm one, and suggests the design of nonpeptidic small molecule mimetics fo r EPO and other cytokines may indeed be achievable.