THE X-RAY STRUCTURE OF A GROWTH-HORMONE PROLACTIN RECEPTOR COMPLEX

THE human pituitary hormones, growth hormone (hGH) and prolactin (hPRL ), regulate a large variety of physiological processes, among which ar e growth and differentiation of muscle, bone and cartilage cells, and lactation(1). These activities are initiated by hormone-receptor bindi ng. The hGH and hPRL receptors (hGH(R) and hPRL(R), respectively) are single-pass transmembrane receptors from class 1 of the haematopoietic receptor superfamily(2,3). This classification is based on sequence s imilarity in their extracellular domains, notably a highly conserved p entapeptide, the so-called 'WSXWS box', the function of which is contr oversial. All ligands in class 1 activate their respective receptors b y clustering mechanisms(4). In the case of hGH, activation involves re ceptor homodimerization in a sequential process: the active ternary co mplex containing one ligand and two receptor molecules is formed by as sociation of a receptor molecule to an intermediate 1:1 complex(5-8). hPRL does not bind to the hGH receptor, but hGH binds to both the hGH( R) and hPRL(R), and mutagenesis studies have shown that the receptor-b inding sites on hGH overlap(9). We present here the crystal structure of the 1:1 complex of hGH bound to the extracellular domain of the hPR L(R). Comparisons with the hGH-hGH(R) complex(10) reveal how hGH can b ind to the two distinctly different receptor binding surfaces.