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- PDB-9c7y: Structure Of Respiratory Syncytial Virus Polymerase in complex wi... -

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Basic information

Entry
Database: PDB / ID: 9c7y
TitleStructure Of Respiratory Syncytial Virus Polymerase in complex with JNJ-2729
Components
  • Phosphoprotein
  • RNA-directed RNA polymerase L
KeywordsVIRAL PROTEIN / TRANSFERASE/INHIBITOR / Non-Nucleoside Inhibitor / complex / Polymerase / RSV / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


NNS virus cap methyltransferase / Respiratory syncytial virus genome transcription / GDP polyribonucleotidyltransferase / Translation of respiratory syncytial virus mRNAs / 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 ...NNS virus cap methyltransferase / Respiratory syncytial virus genome transcription / GDP polyribonucleotidyltransferase / Translation of respiratory syncytial virus mRNAs / 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 / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / host cell cytoplasm / 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 / Mononegavirales RNA-directed RNA polymerase catalytic domain / Mononegavirus L protein 2-O-ribose methyltransferase / Mononegavirales mRNA-capping domain V / RNA-directed RNA polymerase L, C-terminal / Mononegavirales RNA dependent RNA polymerase ...Phosphoprotein, pneumoviral / Pneumovirus phosphoprotein / RNA-directed RNA polymerase L methyltransferase domain, rhabdovirus / Virus-capping methyltransferase, MT domain / RNA-directed RNA polymerase, paramyxovirus / Mononegavirales RNA-directed RNA polymerase catalytic domain / Mononegavirus L protein 2-O-ribose methyltransferase / Mononegavirales mRNA-capping domain V / RNA-directed RNA polymerase L, C-terminal / Mononegavirales RNA dependent RNA polymerase / Mononegavirales mRNA-capping region V / RdRp of negative ssRNA viruses with non-segmented genomes catalytic domain profile. / Mononegavirus L protein 2'-O-ribose methyltransferase domain profile.
Similarity search - Domain/homology
: / Phosphoprotein / RNA-directed RNA polymerase L
Similarity search - Component
Biological speciesHuman respiratory syncytial virus A2
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.24 Å
AuthorsYin, Y. / Tran, M.T. / Yu, X. / Jonckers, T.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: ACS Med Chem Lett / Year: 2024
Title: Structure-Activity Relationship of Oxacyclo- and Triazolo-Containing Respiratory Syncytial Virus Polymerase Inhibitors.
Authors: Minh T Tran / Sandrine Grosse / Rodrigo J Carbajo / Edgar Jacoby / Yanting Yin / Xiaodi Yu / Carol Martinez / Bart Stoops / Ludwig Cooymans / Lili Hu / Ferdinand H Lutter / Serge Pieters / ...Authors: Minh T Tran / Sandrine Grosse / Rodrigo J Carbajo / Edgar Jacoby / Yanting Yin / Xiaodi Yu / Carol Martinez / Bart Stoops / Ludwig Cooymans / Lili Hu / Ferdinand H Lutter / Serge Pieters / Eric Tan / Jesus Alcázar / Dirk Roymans / Herman van Vlijmen / Peter Rigaux / Sujata Sharma / Tim H M Jonckers /
Abstract: Despite the availability of medicines preventing respiratory syncytial virus (RSV) infection, post-exposure treatment options are needed for addressing patient's needs. RSV non-nucleoside polymerase ...Despite the availability of medicines preventing respiratory syncytial virus (RSV) infection, post-exposure treatment options are needed for addressing patient's needs. RSV non-nucleoside polymerase inhibitors (NNI) have emerged as a promising asset for which our group previously disclosed JNJ-8003 with potent antiviral activity and pronounced efficacy. In this work, a structural-guided design to modify the linker vector of JNJ-8003 resulted in the identification of 2-oxacyclo pyridine-containing derivatives whose various ring closing strategies are described. In addition, bioisosteric replacement of an amide bond with triazole retained potency, and cryo-electron microscopy (cryo-EM) confirmed binding in the capping domain. Subsequent NMR conformational analysis suggested a correlation between the potency and conformations. Our efforts have fulfilled the aim of identifying linker modifications with maintained biological activity while enriching structural diversity and allowing modulations of other parameters.
History
DepositionJun 11, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 8, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)371,3206
Polymers370,7345
Non-polymers5861
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 / 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 A2 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P28887, RNA-directed RNA polymerase, mRNA (guanine-N7)-methyltransferase, Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases, GDP polyribonucleotidyltransferase
#2: Protein
Phosphoprotein / Protein P


Mass: 29062.895 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human respiratory syncytial virus A2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P03421
#3: Chemical ChemComp-A1AWZ / (2S)-1,1,1-trifluoro-2-[5-fluoro-6-(4-fluorophenyl)-4-(2-hydroxypropan-2-yl)pyridin-2-yl]-3-[(4M)-4-(8-methoxyquinolin-6-yl)-1H-1,2,3-triazol-1-yl]propan-2-ol / JNJ-2729


Mass: 585.525 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H24F5N5O3 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
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: Respiratory syncytial virus polymerase in complex with non-nucleoside inhibitor
Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Human respiratory syncytial virus A2
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
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: 3.24 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 267890 / Symmetry type: POINT

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