7el9
Structure of Machupo virus L polymerase in complex with Z protein and 3'-vRNA (dimeric complex)
Structural highlights
FunctionQ6IVU0_MACHU RNA-dependent RNA polymerase which is responsible for replication and transcription of the viral RNA genome. During transcription, synthesizes 4 subgenomic RNAs, and assures their capping by a cap-snatching mechanism, in which cellular capped pre-mRNAs are used to generate primers for viral transcription. The 3'-end of subgenomic mRNAs molecules are heterogeneous and not polyadenylated. The replicase function is to direct synthesis of antigenomic and genomic RNA which are encapsidated and non capped. As a consequence of the use of the same enzyme for both transcription and replication, these mechanisms need to be well coordinated. These processes may be regulated by proteins N and Z in a dose-dependent manner.[HAMAP-Rule:MF_04086][PIRNR:PIRNR000836] Publication Abstract from PubMedZoonotic 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 A 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. Cryo-EM structures of Lassa and Machupo virus polymerases complexed with cognate regulatory Z proteins identify targets for antivirals.,Xu X, Peng R, Peng Q, Wang M, Xu Y, Liu S, Tian X, Deng H, Tong Y, Hu X, Zhong J, Wang P, Qi J, Gao GF, Shi Y Nat Microbiol. 2021 Jul;6(7):921-931. doi: 10.1038/s41564-021-00916-w. Epub 2021 , Jun 14. PMID:34127846[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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