Corcoran William K, Cosio Amparo, Edelstein Hailey I, Leonard Joshua N
Department of Chemical and Biological Engineering, Northwestern University, Evanston, Illinois 60208, United States.
Interdisciplinary Biological Sciences Program, Northwestern University, Evanston, Illinois 60208, United States.
GEN Biotechnol. 2025 Feb;4(1):37-55. doi: 10.1089/genbio.2024.0057. Epub 2025 Feb 17.
Engineered receptors play increasingly important roles in transformative cell-based therapies. However, the structural mechanisms that drive differences in performance across receptor designs are often poorly understood. Recent advances in protein structural prediction tools have enabled the modeling of virtually any user-defined protein, but how these tools might build understanding of engineered receptors has yet to be fully explored. In this study, we employed structural modeling tools to perform post hoc analyses to investigate whether predicted structural features might explain observed functional variation. We selected a recently reported library of receptors derived from natural cytokine receptors as a case study, generated structural models, and from these predictions quantified a set of structural features that plausibly impact receptor performance. Encouragingly, for a subset of receptors, structural features explained considerable variation in performance, and trends were largely conserved across structurally diverse receptor sets. This work indicates potential for structure prediction-guided synthetic receptor engineering.
工程化受体在变革性的细胞疗法中发挥着越来越重要的作用。然而,驱动不同受体设计性能差异的结构机制往往鲜为人知。蛋白质结构预测工具的最新进展使得几乎任何用户定义的蛋白质都能进行建模,但这些工具如何增进对工程化受体的理解尚未得到充分探索。在本研究中,我们使用结构建模工具进行事后分析,以研究预测的结构特征是否可以解释观察到的功能变异。我们选择了一个最近报道的源自天然细胞因子受体的受体文库作为案例研究,生成了结构模型,并从这些预测中量化了一组可能影响受体性能的结构特征。令人鼓舞的是,对于一部分受体,结构特征解释了相当大的性能差异,并且趋势在结构多样的受体组中基本保持一致。这项工作表明了结构预测指导合成受体工程的潜力。