title: Use of a model to understand prolactin and growth hormone specificities.
abstract: A human prolactin (hPRL) model based on a 2.1 A resolution X-ray refinement of porcine growth hormone is reported. Only regions clearly defined in the growth hormone template (the four-helix bundle) or previously assumed to be involved in hPRL-receptor binding (the bundle and the binding site loop) are included. A description of the model construction is provided and the resulting hPRL structure is used to interpret mutation/activity data for the cross-reactivity of human growth hormone (hGH) with the lactogenic receptor and the binding of human and bovine prolactin to the lactogenic receptor. The recognition of hPRL by its receptor unexpectedly appears to resemble more closely the interaction of hGH with the somatogenic receptor than with the lactogenic receptor. Each hGH binds to two receptor molecules, and an essential second messenger mediated by correct formation of the receptor-receptor interface has been proposed. The absence of receptor cross-reactivity for hPRL is linked to key sequence changes in hPRL which could disrupt hPRL-somatogenic receptor binding at the second site. A number of previous experiments have relied on the assumption that bioactivity is mediated by homologous residues at topologically equivalent positions. According to the model, this does not appear to be strictly true at either binding site. Good correlation at equivalent positions may be restricted to residues that are important for maintaining binding site shape as well as providing complementary stabilizing interactions between the hormone and receptor. Experiments are proposed to test our hypotheses.
authors.affiliation: Laboratory of Molecular Biology and Genetic Engineering, University of Liege, Sart-Tilman, Belgium.
authors.forename: V
authors.initials: V
authors.lastname: Goffin
authors.forename: J A
authors.initials: JA
authors.lastname: Martial
authors.forename: N L
authors.initials: NL
authors.lastname: Summers
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D003196:Computer Graphics; D013006:Growth Hormone / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed / Q000235:genetics; D011388:Prolactin / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011981:Receptors, Prolactin / Q000378:metabolism; D016415:Sequence Alignment; D013552:Swine / Q000378:metabolism
chemical_list: D011981:Receptors, Prolactin; D011388:Prolactin; D013006:Growth Hormone