Rapid and accurate deorphanization of ligand-receptor pairs using AlphaFold

Banhos Danneskiold-Samsoee, N.; Kavi, D.; Jude, K. M.; Nissen, S. B.; Wat, L. W.; Coassolo, L.; Zhao, M.; Asae Santana-Oikawa, G.; Broido, B. B.; Garcia, K. C.; Svensson, K. J.

doi:10.1101/2023.03.16.531341

bioRxiv · 10.1101/2023.03.16.531341

Rapid and accurate deorphanization of ligand-receptor pairs using AlphaFold

Banhos Danneskiold-Samsoee, N.·Kavi, D.·Jude, K. M.·Nissen, S. B.·Wat, L. W.·Coassolo, L.·Zhao, M.·Asae Santana-Oikawa, G.·Broido, B. B.·Garcia, K. C.·Svensson, K. J.

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Abstract

Secreted proteins play crucial roles in paracrine and endocrine signaling; however, identifying novel ligand-receptor interactions remains challenging. Here, we benchmarked AlphaFold as a screening approach to identify extracellular ligand-binding pairs using a structural library of single-pass transmembrane receptors. Key to the approach is the optimization of AlphaFold input and output for screening ligands against receptors to predict the most probable ligand-receptor interactions. Importantly, the predictions were performed on ligand-receptor pairs not used for AlphaFold 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. These results demonstrate 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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Banhos Danneskiold-Samsoee, N., Kavi, D., Jude, K. M., Nissen, S. B., Wat, L. W., Coassolo, L., Zhao, M., Asae Santana-Oikawa, G., Broido, B. B., Garcia, K. C., Svensson, K. J.. 2023-03-17. Rapid and accurate deorphanization of ligand-receptor pairs using AlphaFold. https://doi.org/10.1101/2023.03.16.531341

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