A versatile insulin analog with high potency for both insulin and insulin-like growth factor 1 receptors: Structural implications for receptor binding

• Published in: The Journal of biological chemistry Vol. 293; no. 43; pp. 16818 - 16829
• Main Authors: Chrudinová, Martina, Žáková, Lenka, Marek, Aleš, Socha, Ondřej, Buděšínský, Miloš, Hubálek, Martin, Pícha, Jan, Macháčková, Kateřina, Jiráček, Jiří, Selicharová, Irena
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.10.2018; American Society for Biochemistry and Molecular Biology
• Subjects: Amino Acid Sequence; binding; Crystallography, X-Ray; Humans; insulin; Insulin - agonists; Insulin - metabolism; insulin receptor; insulin-like growth factor (IGF); Insulin-Like Growth Factor I - chemistry; Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor I - metabolism; Kinetics; Protein Binding; protein design; Protein Structure and Folding; Receptor, IGF Type 1; Receptor, Insulin - chemistry; Receptor, Insulin - genetics; Receptor, Insulin - metabolism; Receptors, Somatomedin - chemistry; Receptors, Somatomedin - genetics; Receptors, Somatomedin - metabolism; Site 1; structure-function; insulin; insulin-like growth factor (IGF); structure-function; Site 1; binding; insulin receptor; kinetics; protein design
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.RA118.004852

Insulin and insulin-like growth factor 1 (IGF-1) are closely related hormones involved in the regulation of metabolism and growth. They elicit their functions through activation of tyrosine kinase–type receptors: insulin receptors (IR-A and IR-B) and IGF-1 receptor (IGF-1R). Despite similarity in primary and three-dimensional structures, insulin and IGF-1 bind the noncognate receptor with substantially reduced affinity. We prepared [d-HisB24, GlyB31, TyrB32]-insulin, which binds all three receptors with high affinity (251 or 338% binding affinity to IR-A respectively to IR-B relative to insulin and 12.4% binding affinity to IGF-1R relative to IGF-1). We prepared other modified insulins with the aim of explaining the versatility of [d-HisB24, GlyB31, TyrB32]-insulin. Through structural, activity, and kinetic studies of these insulin analogs, we concluded that the ability of [d-HisB24, GlyB31, TyrB32]-insulin to stimulate all three receptors is provided by structural changes caused by a reversed chirality at the B24 combined with the extension of the C terminus of the B chain by two extra residues. We assume that the structural changes allow the directing of the B chain C terminus to some extra interactions with the receptors. These unusual interactions lead to a decrease of dissociation rate from the IR and conversely enable easier association with IGF-1R. All of the structural changes were made at the hormones' Site 1, which is thought to interact with the Site 1 of the receptors. The results of the study suggest that merely modifications of Site 1 of the hormone are sufficient to change the receptor specificity of insulin.