9qtb
Apo form of the L protein from Rift Valley Fever Virus
Structural highlights
FunctionA2SZS1_RVFVZ RNA-dependent RNA polymerase, which is responsible for the replication and transcription of the viral RNA genome using antigenomic RNA as an intermediate. During transcription, synthesizes subgenomic RNAs and assures their capping by a cap-snatching mechanism, which involves the endonuclease activity cleaving the host capped pre-mRNAs. These short capped RNAs are then used as primers for viral transcription. The 3'-end of subgenomic mRNAs molecules are not polyadenylated. During replication, the polymerase binds the 5' and 3' vRNA extremities at distinct sites. In turn, significant conformational changes occur in the polymerase and in vRNA to initiate active RNA synthesis. As a consequence of the use of the same enzyme for both transcription and replication, these mechanisms need to be well coordinated.[ARBA:ARBA00046037] Publication Abstract from PubMedRift Valley fever virus (RVFV) is an arbovirus from the Phenuiviridae family that can cause severe disease in humans and livestock, with outbreaks resulting in substantial economic losses. Despite the availability of attenuated vaccines for animals, there is no approved preventive or therapeutic agent for human RVFV infections. Moreover, the safety and efficacy of the current veterinary vaccines remain uncertain. The RVFV L protein, a 250 kDa polymerase, plays a key role in viral replication and transcription, containing endonuclease, RNA-dependent RNA polymerase (RdRp), and cap-binding domains. Structurally conserved across related viruses and functionally analogous to the influenza virus polymerase, the L protein is a compelling antiviral target. In our study, we screened a library of polymerase inhibitors and identified several compounds with inhibitory activity against the RVFV polymerase. We validated their effect using both live virus assays and a minigenome luciferase reporter system. Resistance mutants were generated, and key mutations conferring resistance to the inhibitors were identified and characterized. Some of these key mutations were structurally analyzed via cryo-electron microscopy, using a new structure of the apo form of wild-type RVFV L protein resolved at 3.5 A. This structure provides critical insights into how the mutations can influence inhibitor binding and RVFV polymerase function. These findings provide insight into how these mutations may confer resistance by affecting inhibitor binding and polymerase activity. Targeting the Rift Valley Fever Virus Polymerase: Resistance Mechanisms and Structural Insights.,Kral' M, Das A, Kotacka T, Blahosova A, Liscakova V, Hodek J, Konvalinka J, Demo G, Kozisek M ACS Infect Dis. 2025 Oct 30. doi: 10.1021/acsinfecdis.5c00832. PMID:41166549[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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