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Rational steering of insulin binding specificity by intra-chain chemical crosslinking
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SYSNO ASEP 0458657 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Rational steering of insulin binding specificity by intra-chain chemical crosslinking Author(s) Viková, Jitka (UOCHB-X)
Collinsová, Michaela (UOCHB-X) RID
Kletvíková, Emília (UOCHB-X)
Buděšínský, Miloš (UOCHB-X) RID, ORCID
Kaplan, V. (CZ)
Žáková, Lenka (UOCHB-X) RID, ORCID
Veverka, Václav (UOCHB-X) RID, ORCID
Hexnerová, Rozálie (UOCHB-X) ORCID, RID
Tarazona Avinó, R. J. (ES)
Straková, Jana (UOCHB-X)
Selicharová, Irena (UOCHB-X) RID, ORCID
Vaněk, Václav (UOCHB-X) RID, ORCID
Wright, D. W. (GB)
Watson, C. J. (GB)
Turkenburg, J. P. (GB)
Brzozowski, A. M. (GB)
Jiráček, Jiří (UOCHB-X) RID, ORCIDArticle number 19431 Source Title Scientific Reports. - : Nature Publishing Group - ISSN 2045-2322
Roč. 6, Jan 21 (2016)Number of pages 12 s. Language eng - English Country GB - United Kingdom Keywords insulin ; insulin receptor ; diabetes ; protein design ; protein synthesis Subject RIV CE - Biochemistry R&D Projects LK11205 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LO1304 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Institutional support UOCHB-X - RVO:61388963 UT WOS 000368775800001 EID SCOPUS 84955617718 DOI 10.1038/srep19431 Annotation 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 Cu-I-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. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434 Year of Publishing 2017 Electronic address http://www.nature.com/articles/srep19431
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