title: Engineering human glycoprotein hormone superactive analogues.
abstract: We report the generation of superactive analogues of human glycoprotein hormones, with potential applications in thyroid and reproductive disorders. Current biological and structural data were used to rationalize mutagenesis. The 11-20 region in the alpha-subunit with a cluster of lysine residues forms a previously unrecognized domain critical for receptor binding and signal transduction, as well as an important motif in the evolution of glycoprotein hormone activities. The gradual elimination of basic residues in the alpha-subunit coincided with the evolutionary divergence of the hominids from the Old World monkeys. By selective reconstitution of certain critical residues present in homologous nonhuman hormones we have developed human thyroid stimulating hormone and chorionic gonadotropin analogues with substantial increases in receptor binding affinity and bioactivity, thus providing a paradigm for the design of novel therapeutic protein analogues.
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore 21201, USA. szkudlin@umbi.umd.edu
authors.forename: M W
authors.initials: MW
authors.lastname: Szkudlinski
authors.forename: N G
authors.initials: NG
authors.lastname: Teh
authors.forename: M
authors.initials: M
authors.lastname: Grossmann
authors.forename: J E
authors.initials: JE
authors.lastname: Tropea
authors.forename: B D
authors.initials: BD
authors.lastname: Weintraub
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001709:Biotechnology; D002460:Cell Line; D006063:Chorionic Gonadotropin / Q000737:chemistry / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D015195:Drug Design; D019143:Evolution, Molecular; D006023:Glycoproteins / Q000737:chemistry* / Q000235:genetics*; D006728:Hormones / Q000737:chemistry* / Q000235:genetics*; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D015202:Protein Engineering; D013972:Thyrotropin / Q000031:analogs & derivatives / Q000737:chemistry / Q000235:genetics
chemical_list: D006063:Chorionic Gonadotropin; D017931:DNA Primers; D006023:Glycoproteins; D006728:Hormones; D013972:Thyrotropin