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 are growth and differentiation of muscle, bone and cartilage cells, and lactation. These activities are initiated by hormone-receptor binding. The hGH and hPRL receptors (hGHR and hPRLR, respectively) are single-pass transmembrane receptors from class 1 of the haematopoietic receptor superfamily. This classification is based on sequence similarity in their extracellular domains, notably a highly conserved pentapeptide, the so-called 'WSXWS box', the function of which is controversial. All ligands in class 1 activate their respective receptors by clustering mechanisms. In the case of hGH, activation involves receptor homodimerization in a sequential process: the active ternary complex containing one ligand and two receptor molecules is formed by association of a receptor molecule to an intermediate 1:1 complex. hPRL does not bind to the hGH receptor, but hGH binds to both the hGHR and hPRLR, and mutagenesis studies have shown that the receptor-binding sites on hGH overlap. We present here the crystal structure of the 1:1 complex of hGH bound to the extracellular domain of the hPRLR. Comparisons with the hGH-hGHR complex reveal how hGH can bind to the two distinctly different receptor binding surfaces.
Somers
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Genentech Inc., Department of Protein Engineering, South San Francisco, California 94080.
Ultsch
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M
De Vos
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AM
Kossiakoff
A A
AA
D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D013006:Growth Hormone / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011981:Receptors, Prolactin / Q000737:chemistry* / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000737:chemistry / Q000378:metabolism
D011981:Receptors, Prolactin; D011986:Receptors, Somatotropin; D013006:Growth Hormone