title: Mutants of human insulin-like growth factor I with reduced affinity for the type 1 insulin-like growth factor receptor.
abstract: Four mutants of human insulin-like growth factor I (hIGF I) have been purified from the conditioned media of yeast transformed with an expression vector containing a synthetic gene for hIGF I altered by site-directed mutagenesis. hIGF I has the sequence Phe-23-Tyr-24-Phe-25 which is homologous to a region in the B-chain of insulin. [Phe23,Phe24,Tyr25]IGF I, in which the sequence is altered to exactly correspond to the homologous sequence in insulin, is equipotent to hIGF I at the types 1 and 2 IGF and insulin receptors. [Leu24]IGF I and [Ser24]IGF I have 32- and 16-fold less affinity than hIGF I at the human placental type 1 IGF receptor, respectively. These peptides are 10- and 2-fold less potent at the placental insulin receptor, respectively. [Leu24]IGF I and [Ser24]IGF I have similarly reduced affinities for the type 1 IGF receptor of rat A10 and mouse L cells. Thus, the importance of the interaction of residue 24 with the receptor is conserved in several species. In three cell-based assays, [Leu24]IGF I and [Ser24]IGF I are full agonists with reduced efficacy compared to hIGF I. Desoctapeptide [Leu24]IGF I, in which the loss of aromaticity at position 24 is combined with the deletion of the carboxyl-terminal D region of hIGF I, has 3-fold lower affinity than [Leu24]IGF I for the type 1 receptor and 2-fold higher affinity for the insulin receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Biochemical Endocrinology, Merck Sharp & Dohme Research Laboratories, Rahway, New Jersey 07065.
authors.forename: M A
authors.initials: MA
authors.lastname: Cascieri
authors.forename: G G
authors.initials: GG
authors.lastname: Chicchi
authors.forename: J
authors.initials: J
authors.lastname: Applebaum
authors.forename: N S
authors.initials: NS
authors.lastname: Hayes
authors.forename: B G
authors.initials: BG
authors.lastname: Green
authors.forename: M L
authors.initials: ML
authors.lastname: Bayne
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D004262:DNA Restriction Enzymes; D005260:Female; D005796:Genes; D005813:Genes, Synthetic; D005822:Genetic Vectors; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism; D007700:Kinetics; D008969:Molecular Sequence Data; D009154:Mutation; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011972:Receptor, Insulin / Q000378:metabolism*; D017451:Receptors, Somatomedin; D013002:Somatomedins / Q000235:genetics*; D013329:Structure-Activity Relationship
chemical_list: D009838:Oligodeoxyribonucleotides; D017451:Receptors, Somatomedin; D013002:Somatomedins; D007334:Insulin-Like Growth Factor I; D011972:Receptor, Insulin; D004262:DNA Restriction Enzymes