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A versatile insulin analog with high potency for both insulin and insulin-like growth factor 1 receptors: Structural implications for receptor binding
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SYSNO ASEP 0498264 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název A versatile insulin analog with high potency for both insulin and insulin-like growth factor 1 receptors: Structural implications for receptor binding Tvůrce(i) Chrudinová, Martina (UOCHB-X) RID, ORCID
Žáková, Lenka (UOCHB-X) RID, ORCID
Marek, Aleš (UOCHB-X) RID, ORCID
Socha, Ondřej (UOCHB-X) ORCID, RID
Buděšínský, Miloš (UOCHB-X) RID, ORCID
Hubálek, Martin (UOCHB-X) RID, ORCID
Pícha, Jan (UOCHB-X) RID, ORCID
Macháčková, Kateřina (UOCHB-X)
Jiráček, Jiří (UOCHB-X) RID, ORCID
Selicharová, Irena (UOCHB-X) RID, ORCIDZdroj.dok. Journal of Biological Chemistry. - : Elsevier - ISSN 0021-9258
Roč. 293, č. 43 (2018), s. 16818-16829Poč.str. 12 s. Jazyk dok. eng - angličtina Země vyd. US - Spojené státy americké Klíč. slova insulin ; insulin-like growth factor (IGF) ; structure-function ; insulin receptor ; protein design ; kinetics ; binding ; Site 1 Vědní obor RIV CE - Biochemie Obor OECD Biochemistry and molecular biology CEP EF16_019/0000729 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy Institucionální podpora UOCHB-X - RVO:61388963 UT WOS 000448515100022 EID SCOPUS 85055616917 DOI 10.1074/jbc.RA118.004852 Anotace 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. Pracoviště Ústav organické chemie a biochemie Kontakt asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Rok sběru 2019 Elektronická adresa http://www.jbc.org/content/293/43/16818.full
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