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- PDB-9ed2: CryoEM map of Respiratory Syncytial Virus Polymerase with Non-Nuc... -

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Basic information

Entry
Database: PDB / ID: 9ed2
TitleCryoEM map of Respiratory Syncytial Virus Polymerase with Non-Nucleoside Inhibitor compound 21
Components
  • Compound 21
  • Phosphoprotein
  • RNA-directed RNA polymerase L
KeywordsVIRAL PROTEIN/INHIBITOR / Non-Nucleoside Inhibitor / complex / Polymerase / RSV / VIRAL PROTEIN / VIRAL PROTEIN-INHIBITOR complex
Function / homology
Function and homology information


Respiratory syncytial virus genome transcription / NNS virus cap methyltransferase / Translation of respiratory syncytial virus mRNAs / GDP polyribonucleotidyltransferase / negative stranded viral RNA replication / Respiratory syncytial virus genome replication / RSV-host interactions / Maturation of hRSV A proteins / Assembly and release of respiratory syncytial virus (RSV) virions / Respiratory syncytial virus (RSV) attachment and entry ...Respiratory syncytial virus genome transcription / NNS virus cap methyltransferase / Translation of respiratory syncytial virus mRNAs / GDP polyribonucleotidyltransferase / negative stranded viral RNA replication / Respiratory syncytial virus genome replication / RSV-host interactions / Maturation of hRSV A proteins / Assembly and release of respiratory syncytial virus (RSV) virions / Respiratory syncytial virus (RSV) attachment and entry / Hydrolases; Acting on acid anhydrides; In phosphorus-containing anhydrides / viral life cycle / virion component / symbiont-mediated suppression of host NF-kappaB cascade / host cell cytoplasm / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / RNA-directed RNA polymerase / RNA-directed RNA polymerase activity / GTPase activity / ATP binding / metal ion binding
Similarity search - Function
Phosphoprotein, pneumoviral / Pneumovirus phosphoprotein / RNA-directed RNA polymerase L methyltransferase domain, rhabdovirus / Virus-capping methyltransferase, MT domain / RNA-directed RNA polymerase, paramyxovirus / Mononegavirus L protein 2-O-ribose methyltransferase / RNA-directed RNA polymerase L, C-terminal / Mononegavirus L protein 2'-O-ribose methyltransferase domain profile. / Mononegavirales RNA-directed RNA polymerase catalytic domain / Mononegavirales mRNA-capping domain V ...Phosphoprotein, pneumoviral / Pneumovirus phosphoprotein / RNA-directed RNA polymerase L methyltransferase domain, rhabdovirus / Virus-capping methyltransferase, MT domain / RNA-directed RNA polymerase, paramyxovirus / Mononegavirus L protein 2-O-ribose methyltransferase / RNA-directed RNA polymerase L, C-terminal / Mononegavirus L protein 2'-O-ribose methyltransferase domain profile. / Mononegavirales RNA-directed RNA polymerase catalytic domain / Mononegavirales mRNA-capping domain V / Mononegavirales RNA dependent RNA polymerase / Mononegavirales mRNA-capping region V / RdRp of negative ssRNA viruses with non-segmented genomes catalytic domain profile.
Similarity search - Domain/homology
Phosphoprotein / RNA-directed RNA polymerase L
Similarity search - Component
Biological specieshuman respiratory syncytial virus
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.72 Å
AuthorsYin, Y. / Tran, M.T. / Yu, X. / Jonckers, T. / Carney, S.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J Med Chem / Year: 2025
Title: DNA-Encoded Library Screen Identifies Novel Series of Respiratory Syncytial Virus Polymerase Inhibitors.
Authors: Sean M Carney / Sandrine Grosse / Yanting Yin / Minh T Tran / Jay H Kalin / Edgar Jacoby / Amy Fung / Nicholas Simmons / Xiaoming Xie / Anusarka Bhaumik / Rodrigo J Carbajo / Madison Piassek ...Authors: Sean M Carney / Sandrine Grosse / Yanting Yin / Minh T Tran / Jay H Kalin / Edgar Jacoby / Amy Fung / Nicholas Simmons / Xiaoming Xie / Anusarka Bhaumik / Rodrigo J Carbajo / Madison Piassek / Robyn Miller / Lili Hu / Cynthia Lemmens / Ferdinand H Lutter / Serge Pieters / Geert Rombouts / Irene Vetrano / Daniel Oehlrich / Sonia Tomaso / Kate Lozada / Miguel Osorio Garcia / Brandon Anson / Suzanne De Bruyn / Constance Smith-Monroy / Jean-Marc Neefs / Nádia Conceição-Neto / Bart Kesteleyn / Roberto Fino / Bart Stoops / Herman van Vlijmen / Aaron N Patrick / Xiaodi Yu / Victoria Wong / Daniel J Krosky / Pravien Abeywickrema / Rodrigo F Ortiz-Meoz / Stephen W Mason / Zhinan Jin / Sujata Sharma / Tim H M Jonckers /
Abstract: Respiratory syncytial virus (RSV) remains a public health burden due to unmet therapeutic needs. We recently reported the discovery of a non-nucleoside inhibitor of the RSV polymerase and ...Respiratory syncytial virus (RSV) remains a public health burden due to unmet therapeutic needs. We recently reported the discovery of a non-nucleoside inhibitor of the RSV polymerase and characterized its binding to a novel pocket within the capping domain of the polymerase. Here, we describe our strategy to diversify the chemical matter targeting this site by screening our DNA-encoded chemical libraries, leading to the discovery of a novel and potent series of molecules that inhibits RSV polymerase's biochemical activity, as well as its viral replication in cells. Structural analysis via cryo-EM revealed novel contacts made within the capping domain binding pocket. By leveraging these structural insights for preliminary SAR exploration, we generated analogues for which potency and metabolic stability were improved more than 60- and 40-fold, respectively, over the initial hit. This work provides a path forward for further advanced SAR exploration and development of therapeutics against RSV.
History
DepositionNov 15, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 24, 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
B: Phosphoprotein
C: Phosphoprotein
D: Phosphoprotein
E: Phosphoprotein
G: Compound 21


Theoretical massNumber of molelcules
Total (without water)371,1146
Polymers371,1146
Non-polymers00
Water905
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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


Mass: 254482.750 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) human respiratory syncytial virus / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P28887, RNA-directed RNA polymerase, Hydrolases; Acting on acid anhydrides; In phosphorus-containing anhydrides, GDP polyribonucleotidyltransferase, NNS virus cap methyltransferase
#2: Protein
Phosphoprotein / Protein P


Mass: 29032.844 Da / Num. of mol.: 4 / Mutation: I171V variant
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) human respiratory syncytial virus / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P03421
#3: Protein/peptide Compound 21


Mass: 500.031 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 5 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: CryoEM structure of Respiratory Syncytial Virus Polymerase with Non-Nucleoside Inhibitor compound 21
Type: COMPLEX / Entity ID: #1-#3 / Source: MULTIPLE SOURCES
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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: DIFFRACTION / Nominal defocus max: 2300 nm / Nominal defocus min: 1400 nm
Image recordingElectron dose: 1.368 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.72 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 676690 / Symmetry type: POINT

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