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-Structure paper
タイトル | A general computational design strategy for stabilizing viral class I fusion proteins. |
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ジャーナル・号・ページ | Nat Commun, Vol. 15, Issue 1, Page 1335, Year 2024 |
掲載日 | 2024年2月13日 |
著者 | Karen J Gonzalez / Jiachen Huang / Miria F Criado / Avik Banerjee / Stephen M Tompkins / Jarrod J Mousa / Eva-Maria Strauch / |
PubMed 要旨 | Many pathogenic viruses rely on class I fusion proteins to fuse their viral membrane with the host cell membrane. To drive the fusion process, class I fusion proteins undergo an irreversible ...Many pathogenic viruses rely on class I fusion proteins to fuse their viral membrane with the host cell membrane. To drive the fusion process, class I fusion proteins undergo an irreversible conformational change from a metastable prefusion state to an energetically more stable postfusion state. Mounting evidence underscores that antibodies targeting the prefusion conformation are the most potent, making it a compelling vaccine candidate. Here, we establish a computational design protocol that stabilizes the prefusion state while destabilizing the postfusion conformation. With this protocol, we stabilize the fusion proteins of the RSV, hMPV, and SARS-CoV-2 viruses, testing fewer than a handful of designs. The solved structures of these designed proteins from all three viruses evidence the atomic accuracy of our approach. Furthermore, the humoral response of the redesigned RSV F protein compares to that of the recently approved vaccine in a mouse model. While the parallel design of two conformations allows the identification of energetically sub-optimal positions for one conformation, our protocol also reveals diverse molecular strategies for stabilization. Given the clinical significance of viruses using class I fusion proteins, our algorithm can substantially contribute to vaccine development by reducing the time and resources needed to optimize these immunogens. |
リンク | Nat Commun / PubMed:38351001 / PubMed Central |
手法 | EM (単粒子) / X線回折 |
解像度 | 2.41 - 3.72 Å |
構造データ | EMDB-29035, PDB-8fez: PDB-7tn1: PDB-8e15: |
化合物 | ChemComp-NAG: ChemComp-HOH: |
由来 |
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キーワード | VIRAL PROTEIN / Respiratory syncytial virus / Fusion protein / Human metapneumovirus / computational stabilization / prefusion state |