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

0498264 - ÚOCHB 2019 RIV US eng J - Článek v odborném periodiku
Chrudinová, Martina - Žáková, Lenka - Marek, Aleš - Socha, Ondřej - Buděšínský, Miloš - Hubálek, Martin - Pícha, Jan - Macháčková, Kateřina - Jiráček, Jiří - Selicharová, Irena
A versatile insulin analog with high potency for both insulin and insulin-like growth factor 1 receptors: Structural implications for receptor binding.
Journal of Biological Chemistry. Roč. 293, č. 43 (2018), s. 16818-16829. ISSN 0021-9258. E-ISSN 1083-351X
Grant CEP: GA MŠMT(CZ) EF16_019/0000729
Institucionální podpora: RVO:61388963
Klíčová slova: insulin * insulin-like growth factor (IGF) * structure-function * insulin receptor * protein design * kinetics * binding * Site 1
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 4.106, rok: 2018
http://www.jbc.org/content/293/43/16818.full

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-His(B24), Gly(B31), Tyr(B32)]-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-His(B24), Gly(B31), Tyr(B32)]-insulin. Through structural, activity, and kinetic studies of these insulin analogs, we concluded that the ability of [d-His(B24), Gly(B31), Tyr(B32)]-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.
Trvalý link: http://hdl.handle.net/11104/0291126