2019年8月8日，美国华盛顿大学David Baker研究组在《自然》发表论文，报道了生物活性蛋白开关的从头设计。

研究人员通过调控竞争性分子内外的相互作用力，探索了从头设计可切换的蛋白质系统的可能性。研究人员设计了一个具有单一界面的静态五螺旋笼，其可以在分子外与末端门闩螺旋或在分子内与多肽钥匙进行相互作用。编码门闩的是可用于结合、降解或核运输的功能模体，只有当钥匙从笼子中移开门闩才能发挥功能。研究人员在体外、酵母中以及哺乳动物细胞中验证了这个笼子-钥匙系统，通过钥匙可以实现多达40倍的功能激活。通过诱导构象变化实现对可切换蛋白质功能的设计是蛋白质从头设计的一个里程碑，并为合成生物学和细胞工程开辟了新的途径。

研究人员表示，蛋白功能的变构调节在生物钟普遍存在，但对从头蛋白质设计是具有挑战性的，因为这需要对具有相当自由能的多个状态进行精确设计。
 

附：英文原文

Title: De novo design of bioactive protein switches

Author: Robert A. Langan, Scott E. Boyken, Andrew H. Ng, Jennifer A. Samson, Galen Dods, Alexandra M. Westbrook, Taylor H. Nguyen, Marc J. Lajoie, Zibo Chen, Stephanie Berger, Vikram Khipple Mulligan, John E. Dueber, Walter R. P. Novak, Hana El-Samad, David Baker

Issue&Volume:  Volume 572 Issue 7768

Abstract: Allosteric regulation of protein function is widespread in biology, but is challenging for de novo protein design as it requires the explicit design of multiple states with comparable free energies. Here we explore the possibility of designing switchable protein systems de novo, through the modulation of competing inter- and intramolecular interactions. We design a static, five-helix cage with a single interface that can interact either intramolecularly with a terminal latch helix or intermolecularly with a peptide key. Encoded on the latch are functional motifs for binding, degradation or nuclear export that function only when the key displaces the latch from the cage. We describe orthogonal cagekey systems that function in vitro, in yeast and in mammalian cells with up to 40-fold activation of function by key. The ability to design switchable protein functions that are controlled by induced conformational change is a milestone for de novo protein design, and opens up new avenues for synthetic biology and cell engineering.

DOI: 10.1038/s41586-019-1432-8

Source:https://www.nature.com/articles/s41586-019-1432-8