Hormone Receptors: Structures and Functions

0575692 - ÚOCHB 2024 RIV US eng M - Monography Chapter
Jiráček, Jiří - Selicharová, Irena - Žáková, Lenka
Mutations at hypothetical binding site 2 in insulin and insulin-like growth factors 1 and 2.
Hormone Receptors: Structures and Functions. Cambridge: Elsevier, 2023 - (Litwack, G.), s. 187-230. Vitamins and Hormones, 123. ISBN 978-0-443-13455-5
R&D Projects: GA ČR(CZ) GA22-17978S; GA MŠMT(CZ) EF16_019/0000729; GA MŠMT(CZ) LX22NPO5104
Institutional support: RVO:61388963
Keywords : insulin hormones * insulin receptors * binding site
OECD category: Biochemistry and molecular biology
https://doi.org/10.1016/bs.vh.2023.01.010

Elucidating how insulin and the related insulin-like growth factors 1 and 2 (IGF-1 and IGF-2) bind to their cellular receptors (IR and IGF-1R) and how the receptors are activated has been the holy grail for generations of scientists. However, deciphering the 3D structure of tyrosine kinase receptors and their hormone-bound complexes has been complicated by the flexible and dimeric nature of the receptors and the dynamic nature of their interaction with hormones. Therefore, mutagenesis of hormones and kinetic studies first became an important tool for studying receptor interactions. It was suggested that hormones could bind to receptors through two binding sites on the hormone surface called site 1 and site 2. A breakthrough in knowledge came with the solution of cryoelectron microscopy (cryoEM) structures of hormone-receptor complexes. In this chapter, we document in detail the mutagenesis of insulin, IGF-1, and IGF-2 with emphasis on modifications of the hypothetical binding site 2 in the hormones, and we discuss the results of structure-activity studies in light of recent cryoEM structures of hormone complexes with IR and IGF-1R.
Permanent Link: https://hdl.handle.net/11104/0345433