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The functional mimicry of a protein by an unrelated small molecule has
been a formidable challenge. Now, however, the biological activity of a
166-residue hematopoietic growth hormone, erythropoietin (EPO), with its
class 1 cytokine receptor has been mimicked by a 20-residue cyclic
peptide unrelated in sequence to the natural ligand. The crystal
structure at 2.8 A resolution of a complex of this agonist peptide with
the extracellular domain of EPO receptor reveals that a peptide dimer
induces an almost perfect twofold dimerization of the receptor. The
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 induce signal transduction and cell proliferation. The
EPO receptor binding site, defined by peptide interaction, corresponds
to the smaller functional epitope identified for hGH receptor.
Similarly, the EPO mimetic peptide ligand can be considered as a minimal
hormone, and suggests the design of nonpeptidic small molecule mimetics
for EPO and other cytokines may indeed be achievable.
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