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-Structure paper
タイトル | Cryo-EM structures of Lassa and Machupo virus polymerases complexed with cognate regulatory Z proteins identify targets for antivirals. |
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ジャーナル・号・ページ | Nat Microbiol, Vol. 6, Issue 7, Page 921-931, Year 2021 |
掲載日 | 2021年6月14日 |
著者 | Xin Xu / Ruchao Peng / Qi Peng / Min Wang / Ying Xu / Sheng Liu / Xiaolin Tian / Haiteng Deng / Yimin Tong / Xiaoyou Hu / Jin Zhong / Peiyi Wang / Jianxun Qi / George F Gao / Yi Shi / |
PubMed 要旨 | Zoonotic arenaviruses can lead to life-threating diseases in humans. These viruses encode a large (L) polymerase that transcribes and replicates the viral genome. At the late stage of replication, ...Zoonotic arenaviruses can lead to life-threating diseases in humans. These viruses encode a large (L) polymerase that transcribes and replicates the viral genome. At the late stage of replication, the multifunctional Z protein interacts with the L polymerase to shut down RNA synthesis and initiate virion assembly. However, the mechanism by which the Z protein regulates the activity of L polymerase is unclear. Here, we used cryo-electron microscopy to resolve the structures of both Lassa and Machupo virus L polymerases in complex with their cognate Z proteins, and viral RNA, to 3.1-3.9 Å resolutions. These structures reveal that Z protein binding induces conformational changes in two catalytic motifs of the L polymerase, and restrains their conformational dynamics to inhibit RNA synthesis, which is supported by hydrogen-deuterium exchange mass spectrometry analysis. Importantly, we show, by in vitro polymerase reactions, that Z proteins of Lassa and Machupo viruses can cross-inhibit their L polymerases, albeit with decreased inhibition efficiencies. This cross-reactivity results from a highly conserved determinant motif at the contacting interface, but is affected by other variable auxiliary motifs due to the divergent evolution of Old World and New World arenaviruses. These findings could provide promising targets for developing broad-spectrum antiviral drugs. |
リンク | Nat Microbiol / PubMed:34127846 |
手法 | EM (単粒子) |
解像度 | 3.1 - 4.1 Å |
構造データ | EMDB-30387, PDB-7ckl: EMDB-30388, PDB-7ckm: EMDB-31177, PDB-7el9: EMDB-31178, PDB-7ela: EMDB-31179, PDB-7elb: EMDB-31180: Monomeric complex of MACV L bound to Z and 3'-vRNA |
化合物 | ChemComp-MN: ChemComp-ZN: |
由来 |
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キーワード | VIRAL PROTEIN / Lassa virus / Polymerase / Z protein / replication regulation / Machupo virus / VIRAL PROTEIN/RNA / RNA virus / replication / transcription / matrix protein / VIRAL PROTEIN-RNA complex |