瑞士联邦理工学院Barth P.团队报道了通过溶剂介导的变构网络的高信号活性膜受体的计算设计。相关研究成果于2025年1月23日发表在国际顶尖学术期刊《自然—化学》。

蛋白质催化和变构需要残基和配体、溶剂和蛋白质效应分子的原子级编排和运动。然而，通过精确的蛋白质-溶剂协同作用设计蛋白质活性的能力尚未得到证实。

该文中，研究人员报告了14种膜受体的设计，这些受体通过蛋白质内、蛋白质-配体和溶剂分子相互作用的合作网络介导的各种工程变构途径催化G蛋白核苷酸交换。与预测一致，设计的蛋白质活性与柔性跨膜螺旋界面处网络的可塑性水平密切相关。

与相关的天然受体相比，几种设计显示出显著增强的热稳定性和活性。最稳定和最活跃的变体以不可预见的信号活性构象结晶，与设计模型非常一致。最佳设计的变构网络拓扑结构与天然受体的相似性有限，并揭示了比以前从天然蛋白质推断的更大的变构相互作用空间。

该方法应被证明可用于工程化具有新型复合蛋白结合、催化和信号传导活性的蛋白质。

附：英文原文

Title: Computational design of highly signalling-active membrane receptors through solvent-mediated allosteric networks

Author: Chen, K.-Y. M., Lai, J. K., Rudden, L. S. P., Wang, J., Russell, A. M., Conners, K., Rutter, M. E., Condon, B., Tung, F., Kodandapani, L., Chau, B., Zhao, X., Benach, J., Baker, K., Hembre, E. J., Barth, P.

Issue&Volume: 2025-01-23

Abstract: Protein catalysis and allostery require the atomic-level orchestration and motion of residues and ligand, solvent and protein effector molecules. However, the ability to design protein activity through precise protein–solvent cooperative interactions has not yet been demonstrated. Here we report the design of 14 membrane receptors that catalyse G protein nucleotide exchange through diverse engineered allosteric pathways mediated by cooperative networks of intraprotein, protein–ligand and –solvent molecule interactions. Consistent with predictions, the designed protein activities correlated well with the level of plasticity of the networks at flexible transmembrane helical interfaces. Several designs displayed considerably enhanced thermostability and activity compared with related natural receptors. The most stable and active variant crystallized in an unforeseen signalling-active conformation, in excellent agreement with the design models. The allosteric network topologies of the best designs bear limited similarity to those of natural receptors and reveal an allosteric interaction space larger than previously inferred from natural proteins. The approach should prove useful for engineering proteins with novel complex protein binding, catalytic and signalling activities.

DOI: 10.1038/s41557-024-01719-2

Source: https://www.nature.com/articles/s41557-024-01719-2