AlphaFold2 可对单通道受体的配体进行精确的非形态化。

Cell systems Pub Date : 2024-11-20 Epub Date: 2024-11-13 DOI:10.1016/j.cels.2024.10.004
Niels Banhos Danneskiold-Samsøe, Deniz Kavi, Kevin M Jude, Silas Boye Nissen, Lianna W Wat, Laetitia Coassolo, Meng Zhao, Galia Asae Santana-Oikawa, Beatrice Blythe Broido, K Christopher Garcia, Katrin J Svensson
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引用次数: 0

摘要

分泌蛋白在旁分泌和内分泌信号传导中发挥着至关重要的作用;然而,识别配体与受体之间的相互作用仍然具有挑战性。在这里,我们对 AlphaFold2(AF2)进行了基准测试,将其作为一种筛选方法来鉴定单通道跨膜受体的胞外配体。该方法的关键是优化 AF2 的输入和输出,以筛选配体与受体,预测配体与受体之间最可能的相互作用。预测是在未用于 AF2 训练的配体-受体对上进行的。我们展示了很高的判别能力,对已知配体-受体配对的预测成功率接近 90%,对实验验证的各种相互作用的预测成功率为 50%。此外,我们还发现筛选的准确性与配体-受体相互作用的预测并不呈线性关系。这些结果证明了一个快速准确的筛选平台的概念,该平台可通过结构结合预测来预测各种配体的高置信度细胞表面受体,在了解细胞-细胞通讯方面具有潜在的广泛适用性。
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AlphaFold2 enables accurate deorphanization of ligands to single-pass receptors.

Secreted proteins play crucial roles in paracrine and endocrine signaling; however, identifying ligand-receptor interactions remains challenging. Here, we benchmarked AlphaFold2 (AF2) as a screening approach to identify extracellular ligands to single-pass transmembrane receptors. Key to the approach is the optimization of AF2 input and output for screening ligands against receptors to predict the most probable ligand-receptor interactions. The predictions were performed on ligand-receptor pairs not used for AF2 training. We demonstrate high discriminatory power and a success rate of close to 90% for known ligand-receptor pairs and 50% for a diverse set of experimentally validated interactions. Further, we show that screen accuracy does not correlate linearly with prediction of ligand-receptor interaction. These results demonstrate a proof of concept of a rapid and accurate screening platform to predict high-confidence cell-surface receptors for a diverse set of ligands by structural binding prediction, with potentially wide applicability for the understanding of cell-cell communication.

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