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- PDB-9qtb: Apo form of the L protein from Rift Valley Fever Virus -

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Basic information

Entry
Database: PDB / ID: 9qtb
TitleApo form of the L protein from Rift Valley Fever Virus
ComponentsRNA-directed RNA polymerase L
KeywordsVIRAL PROTEIN / Rift Valley Fever Virus / RNA dependent RNA polymerase / L-protein / Replication / Transcription
Function / homology
Function and homology information


nucleoside binding / host cell endoplasmic reticulum / virion component / host cell endoplasmic reticulum-Golgi intermediate compartment / host cell Golgi apparatus / RNA-directed RNA polymerase / viral RNA genome replication / RNA-directed RNA polymerase activity / DNA-templated transcription / metal ion binding
Similarity search - Function
RNA-directed RNA polymerase, phlebovirus / RNA-directed RNA polymerase L, PA-C-like domain / RNA-directed RNA polymerase L, PA-C-like domain / RNA-directed RNA polymerase L, N-terminal / L protein N-terminus / RNA-dependent RNA polymerase, bunyaviral / Bunyavirus RNA dependent RNA polymerase / RNA-directed RNA polymerase, negative-strand RNA virus / RdRp of negative ssRNA viruses with segmented genomes catalytic domain profile.
Similarity search - Domain/homology
RNA-directed RNA polymerase L
Similarity search - Component
Biological speciesRift valley fever virus
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsKral, M. / Das, A.R. / Kotacka, T. / Blahosova, A. / Hodek, J. / Konvalinka, J. / Demo, G. / Kozisek, M.
Funding supportEuropean Union, 1items
OrganizationGrant numberCountry
European Union (EU)LX22NPO5103European Union
CitationJournal: ACS Infect Dis / Year: 2025
Title: Targeting the Rift Valley Fever Virus Polymerase: Resistance Mechanisms and Structural Insights.
Authors: Michal Král' / Amiyaranjan Das / Tomáš Kotačka / Anna Blahošová / Veronika Liščáková / Jan Hodek / Jan Konvalinka / Gabriel Demo / Milan Kožíšek /
Abstract: Rift Valley fever virus (RVFV) is an arbovirus from the family that can cause severe disease in humans and livestock, with outbreaks resulting in substantial economic losses. Despite the ...Rift Valley fever virus (RVFV) is an arbovirus from the 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 Å. 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.
History
DepositionApr 8, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 12, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: RNA-directed RNA polymerase L


Theoretical massNumber of molelcules
Total (without water)241,3231
Polymers241,3231
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein RNA-directed RNA polymerase L / Large structural protein / Replicase / Transcriptase


Mass: 241322.812 Da / Num. of mol.: 1 / Mutation: D103A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rift valley fever virus (STRAIN ZH-548 M12)
Strain: ZH-548
Production host: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
References: UniProt: A2SZS1, RNA-directed RNA polymerase
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Rift Valley Fever Virus L-protein (LPapo) / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.243 MDa / Experimental value: NO
Source (natural)Organism: Rift valley fever virus (STRAIN ZH-548 M12)
Source (recombinant)Organism: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
1100 mMTris-hydrochlorideTris-HCl1
2250 mMSodium ChlorideNaCl1
32 mMDithiothreitolDTT1
SpecimenConc.: 0.48 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: the grid was glow discharged for 45 seconds at 40W power and 5W range using a Gatan Solaris II
Grid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 279.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 1300 nm / Cs: 2.7 mm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 2 sec. / Electron dose: 40 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 9046

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Processing

EM softwareName: PHENIX / Version: 1.21.1_5286: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2403715
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 185424 / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Atomic model building

3D fitting-ID: 1

IDPDB-IDPdb chain-IDAccession codeChain-IDInitial refinement model-IDSource nameType
17EEI

7eei

A7EEIA1PDBexperimental model
2AlphaFoldin silico model

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