Rational steering of insulin binding specificity by intra-chain chemical crosslinking.
Rational steering of insulin binding specificity by intra-chain chemical crosslinking.
复制标题
DOI：
10.1038/srep19431
复制
发表时间：
2016-01-21
影响因子：
4.6
通讯作者：
Jiráček J
中科院分区：
文献类型：
--
作者：
Viková J;Collinsová M;Kletvíková E;Buděšínský M;Kaplan V;Žáková L;Veverka V;Hexnerová R;Tarazona Aviñó RJ;Straková J;Selicharová I;Vaněk V;Wright DW;Watson CJ;Turkenburg JP;Brzozowski AM;Jiráček J
胰岛素是人体代谢的关键激素，对两种类型的糖尿病都具有重要的治疗意义。需要新的具有更多生理特征和更好的血糖控制的胰岛素类似物，特别是优先结合胰岛素受体代谢b -异构体（IR-B）的类似物。在这里，我们的目的是通过在其B22-B30段内的共价链内交联来稳定和调节胰岛素的受体兼容构象，利用cui催化的叠氮化物和炔的Huisgen 1,3-偶极环加成反应。这种方法产生了14种新的系统交联胰岛素类似物，其结构和功能被广泛表征和相关。其中一种类似物含有B26-B29三唑桥，与两种IR亚型的结合都非常活跃，并明显倾向于IR- b。我们的研究结果证明了化学驱动胰岛素功能调节的潜力，也揭示了激素b链c端对其IR-B特异性的功能重要性。
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.