Human growth hormone (hGH) forms a 1:2 complex with the extracellular domain of its receptor-binding protein (hGHbp) as studied by crystallization, size exclusion chromatography, calorimetry, and a previously undescribed fluorescence quenching assay. These and other experiments with protein engineered variants of hGH have led to the identification of the binding determinants for two distinct but adjacent sites on hGH for the hGHbp, and the data indicated that there are two overlapping binding sites on the hGHbp for hGH. Furthermore, the binding of hGH to the hGHbp occurred sequentially; a first hGHbp molecule bound to site 1 on hGH and then a second hGHbp bound to site 2. Hormone-induced receptor dimerization is proposed to be relevant to the signal transduction mechanism for the hGH receptor and other related cytokine receptors.

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Two research articles in this week's Science [Livnah et al . ( p. 464 ) and Wrighton et al . ( p. 458 )] report the isolation and structure of a 20-amino acid peptide that binds to and activates the receptor for erythropoietin but is not derived from the normal ligand. In his Perspective, Wells describes the unique selection procedure that allowed this accomplishment and what it means for drug development.