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
2018
Autori
Machackova, KaterinaChrudinova, Martina
Radosavljević, Jelena
Potalitsyn, Paulo
Krizkova, Kvetoslava
Fabry, Milan
Selicharova, Irena
Collinsova, Michaela
Brzozowski, Andrzej M.
Zakova, Lenka
Jiracek, Jiri
Članak u časopisu (Objavljena verzija)
Metapodaci
Prikaz svih podataka o dokumentuApstrakt
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 analogu...es 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.
Izvor:
Biochemistry, 2018, 57, 16, 2373-2382Izdavač:
- Amer Chemical Soc, Washington
Finansiranje / projekti:
- Czech Academy of Sciences [RVO 61388963, 68378050]
- Medical Research Council [MR/K000179/1]
- Medical Research Council Grant [MR/R009066/1]
- Czech Science Foundation [15-19018S]
Napomena:
- Supplementary material: http://cherry.chem.bg.ac.rs/handle/123456789/3185
DOI: 10.1021/acs.biochem.7b01260
ISSN: 0006-2960
PubMed: 29608283
WoS: 000431088300011
Scopus: 2-s2.0-85045898101
Kolekcije
Institucija/grupa
Hemijski fakultet / Faculty of ChemistryTY - JOUR AU - Machackova, Katerina AU - Chrudinova, Martina AU - Radosavljević, Jelena AU - Potalitsyn, Paulo AU - Krizkova, Kvetoslava AU - Fabry, Milan AU - Selicharova, Irena AU - Collinsova, Michaela AU - Brzozowski, Andrzej M. AU - Zakova, Lenka AU - Jiracek, Jiri PY - 2018 UR - https://cherry.chem.bg.ac.rs/handle/123456789/2135 AB - 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. PB - Amer Chemical Soc, Washington T2 - Biochemistry T1 - 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 VL - 57 IS - 16 SP - 2373 EP - 2382 DO - 10.1021/acs.biochem.7b01260 ER -
@article{ author = "Machackova, Katerina and Chrudinova, Martina and Radosavljević, Jelena and Potalitsyn, Paulo and Krizkova, Kvetoslava and Fabry, Milan and Selicharova, Irena and Collinsova, Michaela and Brzozowski, Andrzej M. and Zakova, Lenka and Jiracek, Jiri", year = "2018", abstract = "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.", publisher = "Amer Chemical Soc, Washington", journal = "Biochemistry", title = "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", volume = "57", number = "16", pages = "2373-2382", doi = "10.1021/acs.biochem.7b01260" }
Machackova, K., Chrudinova, M., Radosavljević, J., Potalitsyn, P., Krizkova, K., Fabry, M., Selicharova, I., Collinsova, M., Brzozowski, A. M., Zakova, L.,& Jiracek, J.. (2018). 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. in Biochemistry Amer Chemical Soc, Washington., 57(16), 2373-2382. https://doi.org/10.1021/acs.biochem.7b01260
Machackova K, Chrudinova M, Radosavljević J, Potalitsyn P, Krizkova K, Fabry M, Selicharova I, Collinsova M, Brzozowski AM, Zakova L, Jiracek J. 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. in Biochemistry. 2018;57(16):2373-2382. doi:10.1021/acs.biochem.7b01260 .
Machackova, Katerina, Chrudinova, Martina, Radosavljević, Jelena, Potalitsyn, Paulo, Krizkova, Kvetoslava, Fabry, Milan, Selicharova, Irena, Collinsova, Michaela, Brzozowski, Andrzej M., Zakova, Lenka, Jiracek, Jiri, "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" in Biochemistry, 57, no. 16 (2018):2373-2382, https://doi.org/10.1021/acs.biochem.7b01260 . .