美国华盛顿大学David Baker课题组提出了易解离的设计使细胞因子信号的定时。该研究于2025年9月24日发表于国际一流学术期刊《自然》杂志上。

在这里，研究人员描述了一种设计系统的一般方法，该系统采用诱导拟合功率冲程来产生结构上的非稳态和应变激发态，以变构方式驱动蛋白质复合物解离。X射线晶体学、双电子-电子共振光谱和动力学结合测量表明，结合激发态可以使效应剂诱导的解离率增加高达5700倍。该课题组人员通过设计快速生物传感器、动力学控制电路和细胞因子模拟物来强调这种方法的力量，这些模拟物可以在几秒钟内与受体分离，从而能够解剖白介素-2信号传导的时间动态。

研究人员表示，蛋白质设计的重点是基态的设计，以确保它们的能量足够低，能够被大量填充。此外，设计一个系统的动力学和动力学还需要设计从一个低洼状态过渡到另一个低洼状态的激发态。这是一项具有挑战性的任务，因为这些状态可能会被充分拉伸到人口稀少，但不会被拉伸到根本没有人口，并且因为大多数蛋白质设计方法都专注于生成接近理想的结构。

附：英文原文

Title: Design of facilitated dissociation enables timing of cytokine signalling

Author: Broerman, Adam J., Pollmann, Christoph, Zhao, Yang, Lichtenstein, Mauriz A., Jackson, Mark D., Tessmer, Maxx H., Ryu, Won Hee, Ogishi, Masato, Abedi, Mohamad H., Sahtoe, Danny D., Allen, Aza, Kang, Alex, De La Cruz, Joshmyn, Brackenbrough, Evans, Sankaran, Banumathi, Bera, Asim K., Zuckerman, Daniel M., Stoll, Stefan, Garcia, K. Christopher, Praetorius, Florian, Piehler, Jacob, Baker, David

Issue&Volume: 2025-09-24

Abstract: Protein design has focused on the design of ground states, ensuring that they are sufficiently low energy to be highly populated1. Designing the kinetics and dynamics of a system requires, in addition, the design of excited states that are traversed in transitions from one low-lying state to another2,3. This is a challenging task because such states must be sufficiently strained to be poorly populated, but not so strained that they are not populated at all, and because protein design methods have focused on generating near-ideal structures4,5,6,7. Here we describe a general approach for designing systems that use an induced-fit power stroke8 to generate a structurally frustrated9 and strained excited state, allosterically driving protein complex dissociation. X-ray crystallography, double electron–electron resonance spectroscopy and kinetic binding measurements show that incorporating excited states enables the design of effector-induced increases in dissociation rates as high as 5,700-fold. We highlight the power of this approach by designing rapid biosensors, kinetically controlled circuits and cytokine mimics that can be dissociated from their receptors within seconds, enabling dissection of the temporal dynamics of interleukin-2 signalling.

DOI: 10.1038/s41586-025-09549-z

Source: https://www.nature.com/articles/s41586-025-09549-z