Počet záznamů: 1
Converting Insulin-like Growth Factors 1 and 2 into High-Affinity Ligands for Insulin Receptor Isoform A by the Introduction of an Evolutionarily Divergent Mutation
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SYSNO ASEP 0489708 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Converting Insulin-like Growth Factors 1 and 2 into High-Affinity Ligands for Insulin Receptor Isoform A by the Introduction of an Evolutionarily Divergent Mutation Tvůrce(i) Macháčková, Kateřina (UOCHB-X)
Chrudinová, Martina (UOCHB-X) RID, ORCID
Radosavljević, Jelena (UOCHB-X) ORCID, RID
Potalitsyn, Pavlo (UOCHB-X) RID, ORCID
Křížková, Květoslava (UOCHB-X)
Fábry, Milan (UMG-J) RID
Selicharová, Irena (UOCHB-X) RID, ORCID
Collinsová, Michaela (UOCHB-X) RID
Brzozowski, A. M. (GB)
Žáková, Lenka (UOCHB-X) RID, ORCID
Jiráček, Jiří (UOCHB-X) RID, ORCIDZdroj.dok. Biochemistry. - : American Chemical Society - ISSN 0006-2960
Roč. 57, č. 16 (2018), s. 2373-2382Poč.str. 10 s. Jazyk dok. eng - angličtina Země vyd. US - Spojené státy americké Klíč. slova insulin-like growth factor ; insulin ; receptor ; analog Vědní obor RIV CE - Biochemie Obor OECD Biochemistry and molecular biology CEP GA15-19018S GA ČR - Grantová agentura ČR Institucionální podpora UOCHB-X - RVO:61388963 ; UMG-J - RVO:68378050 UT WOS 000431088300011 EID SCOPUS 85045898101 DOI 10.1021/acs.biochem.7b01260 Anotace Insulin-like growth factors 1 and 2 (IGF-1 and -2, respectively) are protein hormones involved not only in normal growth and development but also in life span regulation and cancer. They exert their functions mainly through the IGF-1R or by binding to isoform A of the insulin receptor (IR-A). The development of IGF-1 and IGF-2 antagonists is of great clinical interest. Mutations of A4 and A8 sites of human insulin lead to disproportionate effects on hormone IR binding and activation. Here, we systematically modified IGF-1 sites 45, 46, and 49 and IGF-2 sites 45 and 48, which correspond, or are close, to insulin sites A4 and A8. The IGF-1R and IR-A binding and autophosphorylation potencies of these analogues were characterized. They retained the main IGF-1R-related properties, but the hormones with His49 in IGF-1 and His48 in IGF-2 showed significantly higher affinities for IR-A and for IR-B, being the strongest IGF-1- and IGF-2-like binders of these receptors ever reported. All analogues activated IR-A and IGF-1R without major discrepancies in their binding affinities. This study revealed that IR-A and IGF-1R contain specific sites, likely parts of their so-called sites 2', which can interact differently with specifically modified IGF analogues. Moreover, a clear importance of IGF-2 site 44 for effective hormone folding was also observed. These findings may facilitate novel and rational engineering of new hormone analogues for IR-A and IGF-1R studies and for potential medical applications. Pracoviště Ústav organické chemie a biochemie Kontakt asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434 Rok sběru 2019 Elektronická adresa https://pubs.acs.org/doi/10.1021/acs.biochem.7b01260
Počet záznamů: 1