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Preparation of a new insulin analog in order to study the interaction of the hormone with insulin receptor isoforms,
Halamová, Tereza ; Jiráček, Jiří (advisor) ; Obšilová, Veronika (referee)
Insulin acts as a key hormone in the blood glucose levels maintaining mechanisms. Outside this metabolic function it also has a growth hormone functionality. The interaction of insulin with the two existing insulin receptor isoforms - IR-A and IR-B, which are variously represented in the human body is determining insulin. IR-A, supposed to be mainly responsible for the mitogenic function of insulin, is located in the brain or lymphatic cancer and fetal tissue, whereas IR-B, performing metabolic function is located in adipose and muscle tissue. Present aim is to design such insulin analogs that would preferentially bind to IR-B, and could thus more efficiently carry out physiological metabolic function of insulin necessary for patients with diabetes. Based on the recently solved 3D structure of insulin bound to IR, it was found that the C-terminus of the B-chain of insulin must undergo conformational change bending it in about 90ř, for efficient binding to IR. The aim of this thesis was the preparation and characterization of two insulin analogs with bridging C-terminus of the B-chain in positions B26-B29 and B27-B29 using disulfide bridge. This could fix a bended structure of the B chain end and could help to increase the affinity of IR and specificity for IR-B. The preparation was carried out...
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