Rational steering of insulin binding specificity by intra-chain chemical crosslinking
| Autor: | Christopher J. Watson, Rozálie Hexnerová, Václav Vaněk, Jana Straková, Daniel W. Wright, Jiří Jiráček, Emília Kletvíková, Michaela Collinsová, Lenka Žáková, Johan P. Turkenburg, Andrzej M. Brzozowski, Roberto J. Tarazona Aviñó, Jitka Viková, Vojtěch Kaplan, Vaclav Veverka, Miloš Buděšínský, Irena Selicharová |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Models Molecular Azides Protein Conformation medicine.medical_treatment Plasma protein binding Biology 01 natural sciences Article Receptor IGF Type 1 03 medical and health sciences Structure-Activity Relationship Protein structure Insulin receptor substrate medicine Structure–activity relationship Humans Insulin Protein Isoforms Receptor Binding selectivity Genetics Multidisciplinary Cycloaddition Reaction 010405 organic chemistry Protein Stability Receptor Insulin 0104 chemical sciences Insulin receptor 030104 developmental biology Biochemistry Alkynes biology.protein Protein Binding |
| Zdroj: | Scientific Reports 'Scientific Reports ', vol: 6, pages: 19431-1-19431-12 (2016) |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/srep19431 |
| Popis: | Insulin is a key hormone of human metabolism with major therapeutic importance for both types of diabetes. New insulin analogues with more physiological profiles and better glycemic control are needed, especially analogues that preferentially bind to the metabolic B-isoform of insulin receptor (IR-B). Here, we aimed to stabilize and modulate the receptor-compatible conformation of insulin by covalent intra-chain crosslinking within its B22–B30 segment, using the CuI-catalyzed Huisgen 1,3-dipolar cycloaddition reaction of azides and alkynes. This approach resulted in 14 new, systematically crosslinked insulin analogues whose structures and functions were extensively characterized and correlated. One of the analogues, containing a B26–B29 triazole bridge, was highly active in binding to both IR isoforms, with a significant preference for IR-B. Our results demonstrate the potential of chemistry-driven modulation of insulin function, also shedding new light on the functional importance of hormone’s B-chain C-terminus for its IR-B specificity. |
| Databáze: | OpenAIRE |
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