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Rational steering of insulin binding specificity by intra-chain chemical crosslinking

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    0458657 - ÚOCHB 2017 RIV GB eng J - Journal Article
    Viková, Jitka - Collinsová, Michaela - Kletvíková, Emília - Buděšínský, Miloš - Kaplan, V. - Žáková, Lenka - Veverka, Václav - Hexnerová, Rozálie - Tarazona Avinó, R. J. - Straková, Jana - Selicharová, Irena - Vaněk, Václav - Wright, D. W. - Watson, C. J. - Turkenburg, J. P. - Brzozowski, A. M. - Jiráček, Jiří
    Rational steering of insulin binding specificity by intra-chain chemical crosslinking.
    Scientific Reports. Roč. 6, Jan 21 (2016), č. článku 19431. ISSN 2045-2322. E-ISSN 2045-2322
    R&D Projects: GA MŠk(CZ) LK11205; GA MŠk(CZ) LO1304
    Institutional support: RVO:61388963
    Keywords : insulin * insulin receptor * diabetes * protein design * protein synthesis
    Subject RIV: CE - Biochemistry
    Impact factor: 4.259, year: 2016
    http://www.nature.com/articles/srep19431

    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.
    Permanent Link: http://hdl.handle.net/11104/0258905

     
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