Design of a methotrexate-controlled chemical dimerization system and its use in bio-electronic devices.
Design of a methotrexate-controlled chemical dimerization system and its use in bio-electronic devices.
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DOI：
10.1038/s41467-021-27184-w
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发表时间：
2021-12-08
影响因子：
16.6
通讯作者：
Alexandrov K
中科院分区：
文献类型：
--
作者：
Guo Z;Smutok O;Johnston WA;Walden P;Ungerer JPJ;Peat TS;Newman J;Parker J;Nebl T;Hepburn C;Melman A;Suderman RJ;Katz E;Alexandrov K
自然进化产生了选择性识别化学实体及其聚合物的多肽，从离子到蛋白质和核酸。这种选择性相互作用作为生物信号传导和代谢途径的切入点。设计这种入口点的人工版本的能力是合成生物学，生物工程和生物电子学的关键目标。我们着手绘制开发人工小分子的最佳策略：蛋白质复合物作为化学诱导二聚化（CID）系统。使用几个起点，我们进化出了由治疗药物甲氨蝶呤控制的CID系统。对甲氨蝶呤控制的CID系统的生物物理和结构分析揭示了药物诱导的构象变化在配体控制的蛋白质复合物组装中所起的关键作用。我们证明了开发的CID的效用，通过构建甲氨蝶呤的电化学生物传感器，使甲氨蝶呤在人血清中的定量。此外，使用甲氨蝶呤和功能相关的雷帕霉素的生物传感器，我们开发了一个多路复用的生物电子系统，可以执行多个分析物的重复测量。这些结果为构建用于生物电子学和诊断学的遗传编码信号系统以及代谢和信号网络工程打开了大门。人工变构系统的设计工作正在进行中。在这里，作者分析了影响人工小分子发展的因素：作为化学诱导二聚化（CID）系统的蛋白质复合物;他们使用其中一种CID构建甲氨蝶呤的电化学生物传感器。
Natural evolution produced polypeptides that selectively recognize chemical entities and their polymers, ranging from ions to proteins and nucleic acids. Such selective interactions serve as entry points to biological signaling and metabolic pathways. The ability to engineer artificial versions of such entry points is a key goal of synthetic biology, bioengineering and bioelectronics. We set out to map the optimal strategy for developing artificial small molecule:protein complexes that function as chemically induced dimerization (CID) systems. Using several starting points, we evolved CID systems controlled by a therapeutic drug methotrexate. Biophysical and structural analysis of methotrexate-controlled CID system reveals the critical role played by drug-induced conformational change in ligand-controlled protein complex assembly. We demonstrate utility of the developed CID by constructing electrochemical biosensors of methotrexate that enable quantification of methotrexate in human serum. Furthermore, using the methotrexate and functionally related biosensor of rapamycin we developed a multiplexed bioelectronic system that can perform repeated measurements of multiple analytes. The presented results open the door for construction of genetically encoded signaling systems for use in bioelectronics and diagnostics, as well as metabolic and signaling network engineering. Efforts to engineer artificial allosteric systems are ongoing. Here the authors analyse factors influencing development of artificial small molecule:protein complexes that act as chemically induced dimerization (CID) systems; they use one of the CIDs to construct an electrochemical biosensor of methotrexate.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1073/pnas.0801097105
发表时间：
2008-05-06
影响因子：
11.1
作者：
Huang, Jin;Koide, Akiko;Koide, Shohei
通讯作者：
Koide, Shohei
影响因子：
15
作者：
Kang, Shoukai;Davidsen, Kristian;Gu, Liangcai
通讯作者：
Gu, Liangcai
影响因子：
5.4
作者：
Goebel, G.;Schubart, I. W.;Lisdat, F.
通讯作者：
Lisdat, F.
影响因子：
15
作者：
Guo, Zhong;Murphy, Lindy;Alexandrov, Kirill
通讯作者：
Alexandrov, Kirill