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- EMDB-48846: CryoEM structure Of Respiratory Syncytial Virus Polymerase with n... -

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Entry
Database: EMDB / ID: EMD-48846
TitleCryoEM structure Of Respiratory Syncytial Virus Polymerase with novel non-nucleoside inhibitor compound 22
Map dataStructure Of Respiratory Syncytial Virus Polymerase with Novel Non-Nucleoside Inhibitor(Compound 22)
Sample
  • Complex: CryoEM map of Respiratory Syncytial Virus Polymerase with Novel Non-Nucleoside Inhibitor compound 22
    • Protein or peptide: RNA-directed RNA polymerase L
    • Protein or peptide: Phosphoprotein
  • Ligand: 5-(5-bromo-1-methyl-2-oxo-1,2-dihydrospiro[indole-3,4'-piperidin]-1'-yl)-3-chloropyridine-2-carbonitrile
KeywordsNon-Nucleoside Inhibitor / complex / Polymerase / RSV / VIRAL PROTEIN / TRANSFERASE-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
Methodsingle particle reconstruction / cryo EM / Resolution: 2.72 Å
AuthorsYin Y / Yu X / Kalin JH / Tran MT / Sharma S
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: J Virol / Year: 2025
Title: Discovery of a non-nucleoside inhibitor that binds to a novel site in the palm domain of the respiratory syncytial virus RNA-dependent RNA polymerase.
Authors: Jay H Kalin / Yanting Yin / Minh T Tran / Madison Piassek / Amy Fung / Sandrine Grosse / Edgar Jacoby / Anusarka Bhaumik / Suraj Adhikary / Robyn Miller / Cynthia Lemmens / Ferdinand H ...Authors: Jay H Kalin / Yanting Yin / Minh T Tran / Madison Piassek / Amy Fung / Sandrine Grosse / Edgar Jacoby / Anusarka Bhaumik / Suraj Adhikary / Robyn Miller / Cynthia Lemmens / Ferdinand H Lutter / Serge Pieters / Ludwig Cooymans / Geert Rombouts / Daniel Oehlrich / Sonia Tomaso / Kate Lozada / Miguel Osorio Garcia / Brandon Anson / Suzanne De Bruyn / Constance Smith-Monroy / Jean-Marc Neefs / Nádia Conceição-Neto / Bart Stoops / Herman van Vlijmen / Aaron Patrick / Xiaodi Yu / Victoria Wong / Daniel Krosky / Pravien Abeywickrema / Stephen Mason / Zhinan Jin / Tim H M Jonckers / Sujata Sharma /
Abstract: Respiratory syncytial virus (RSV) is a major cause of severe respiratory tract infections in infants, young children, and the elderly. We report herein the discovery and characterization of a novel ...Respiratory syncytial virus (RSV) is a major cause of severe respiratory tract infections in infants, young children, and the elderly. We report herein the discovery and characterization of a novel RSV polymerase (RSVpol) non-nucleoside inhibitor (NNI) chemotype that binds to a previously undescribed, highly conserved site in the palm domain of the L protein. Consistent with the observed mode of inhibition, cryogenic electron microscopy (cryo-EM) revealed the site to be adjacent to the nucleotide binding site. Minireplicon assays confirmed on-target activity against RSVpol, and cell-based antiviral assays showed that the lead compound effectively inhibited viral mRNA transcription and replication in clinically relevant A and B strains. Together, our data provides valuable insights into the molecular basis of inhibition for a novel mechanism of action and paves the way for structure-based design to deliver effective therapeutics against RSV.IMPORTANCERespiratory syncytial virus (RSV) is a negative-sense, single-stranded RNA virus belonging to the family of the order . Currently, monoclonal antibody treatments are only approved for infants, and vaccines are reserved for pregnant women and adults aged 60 years and older. Prophylaxis is also limited to the pediatric patient population, and there are currently no direct antiviral therapies for post-exposure treatment. Viral polymerases are considered well-validated drug targets due to their critical role in transcription and genome replication. Herein, we disclose the discovery of a spiro-indolinone series as polymerase inhibitors and describe the preliminary structure-activity relationship (SAR). A cryogenic electron microscopy (cryo-EM) structure obtained with an optimized lead revealed a novel binding site located in the palm domain, which will enable future structure-based drug design efforts. Novel RSV antivirals could be beneficial both as therapeutics following diagnosis and as a prophylactic in patients less likely to respond to vaccines.
History
DepositionJan 30, 2025-
Header (metadata) releaseMay 28, 2025-
Map releaseMay 28, 2025-
UpdateDec 10, 2025-
Current statusDec 10, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_48846.png

Downloads & links

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Map

FileDownload / File: emd_48846.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationStructure Of Respiratory Syncytial Virus Polymerase with Novel Non-Nucleoside Inhibitor(Compound 22)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.95 Å/pix.
x 288 pix.
= 273.024 Å		0.95 Å/pix.
x 288 pix.
= 273.024 Å		0.95 Å/pix.
x 288 pix.
= 273.024 Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.948 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.245
Minimum - Maximum-2.042684 - 2.9984572
Average (Standard dev.)0.000005055692 (±0.06643958)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 273.02402 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Structure Of Respiratory Syncytial Virus Polymerase with Novel...

Fileemd_48846_half_map_1.map
AnnotationStructure Of Respiratory Syncytial Virus Polymerase with Novel Non-Nucleoside Inhibitor(Compound 22)
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Structure Of Respiratory Syncytial Virus Polymerase with Novel...

Fileemd_48846_half_map_2.map
AnnotationStructure Of Respiratory Syncytial Virus Polymerase with Novel Non-Nucleoside Inhibitor(Compound 22)
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : CryoEM map of Respiratory Syncytial Virus Polymerase with Novel N...

EntireName: CryoEM map of Respiratory Syncytial Virus Polymerase with Novel Non-Nucleoside Inhibitor compound 22
Components
  • Complex: CryoEM map of Respiratory Syncytial Virus Polymerase with Novel Non-Nucleoside Inhibitor compound 22
    • Protein or peptide: RNA-directed RNA polymerase L
    • Protein or peptide: Phosphoprotein
  • Ligand: 5-(5-bromo-1-methyl-2-oxo-1,2-dihydrospiro[indole-3,4'-piperidin]-1'-yl)-3-chloropyridine-2-carbonitrile

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Supramolecule #1: CryoEM map of Respiratory Syncytial Virus Polymerase with Novel N...

SupramoleculeName: CryoEM map of Respiratory Syncytial Virus Polymerase with Novel Non-Nucleoside Inhibitor compound 22
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: human respiratory syncytial virus

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Macromolecule #1: RNA-directed RNA polymerase L

MacromoleculeName: RNA-directed RNA polymerase L / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: RNA-directed RNA polymerase
Source (natural)Organism: human respiratory syncytial virus
Molecular weightTheoretical: 254.48275 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGSWSHPQFE KGSGSGSSWS HPQFEKGSGS LVPRGSMDPI INGNSANVYL TDSYLKGVIS FSECNALGSY IFNGPYLKND YTNLISRQN PLIEHMNLKK LNITQSLISK YHKGEIKLEE PTYFQSLLMT YKSMTSSEQI ATTNLLKKII RRAIEISDVK V YAILNKLG ...String:
MGSWSHPQFE KGSGSGSSWS HPQFEKGSGS LVPRGSMDPI INGNSANVYL TDSYLKGVIS FSECNALGSY IFNGPYLKND YTNLISRQN PLIEHMNLKK LNITQSLISK YHKGEIKLEE PTYFQSLLMT YKSMTSSEQI ATTNLLKKII RRAIEISDVK V YAILNKLG LKEKDKIKSN NGQDEDNSVI TTIIKDDILS AVKDNQSHLK ADKNHSTKQK DTIKTTLLKK LMCSMQHPPS WL IHWFNLY TKLNNILTQY RSNEVKNHGF TLIDNQTLSG FQFILNQYGC IVYHKELKRI TVTTYNQFLT WKDISLSRLN VCL ITWISN CLNTLNKSLG LRCGFNNVIL TQLFLYGDCI LKLFHNEGFY IIKEVEGFIM SLILNITEED QFRKRFYNSM LNNI TDAAN KAQKNLLSRV CHTLLDKTVS DNIINGRWII LLSKFLKLIK LAGDNNLNNL SELYFLFRIF GHPMVDERQA MDAVK INCN ETKFYLLSSL SMLRGAFIYR IIKGFVNNYN RWPTLRNAIV LPLRWLTYYK LNTYPSLLEL TERDLIVLSG LRFYRE FRL PKKVDLEMII NDKAISPPKN LIWTSFPRNY MPSHIQNYIE HEKLKFSESD KSRRVLEYYL RDNKFNECDL YNCVVNQ SY LNNPNHVVSL TGKERELSVG RMFAMQPGMF RQVQILAEKM IAENILQFFP ESLTRYGDLE LQKILELKAG ISNKSNRY N DNYNNYISKC SIITDLSKFN QAFRYETSCI CSDVLDELHG VQSLFSWLHL TIPHVTIICT YRHAPPYIGD HIVDLNNVD EQSGLYRYHM GGIEGWCQKL WTIEAISLLD LISLKGKFSI TALINGDNQS IDISKPIRLM EGQTHAQADY LLALNSLKLL YKEYAGIGH KLKGTETYIS RDMQFMSKTI QHNGVYYPAS IKKVLRVGPW INTILDDFKV SLESIGSLTQ ELEYRGESLL C SLIFRNVW LYNQIALQLK NHALCNNKLY LDILKVLKHL KTFFNLDNID TALTLYMNLP MLFGGGDPNL LYRSFYRRTP DF LTEAIVH SVFILSYYTN HDLKDKLQDL SDDRLNKFLT CIITFDKNPN AEFVTLMRDP QALGSERQAK ITSEINRLAV TEV LSTAPN KIFSKSAQHY TTTEIDLNDI MQNIEPTYPH GLRVVYESLP FYKAEKIVNL ISGTKSITNI LEKTSAIDLT DIDR ATEMM RKNITLLIRI LPLDCNRDKR EILSMENLSI TELSKYVRER SWSLSNIVGV TSPSIMYTMD IKYTTSTISS GIIIE KYNV NSLTRGERGP TKPWVGSSTQ EKKTMPVYNR QVLTKKQRDQ IDLLAKLDWV YASIDNKDEF MEELSIGTLG LTYEKA KKL FPQYLSVNYL HRLTVSSRPC EFPASIPAYR TTNYHFDTSP INRILTEKYG DEDIDIVFQN CISFGLSLMS VVEQFTN VC PNRIILIPKL NEIHLMKPPI FTGDVDIHKL KQVIQKQHMF LPDKISLTQY VELFLSNKTL KSGSHVNSNL ILAHKISD Y FHNTYILSTN LAGHWILIIQ LMKDSKGIFE KDWGEGYITD HMFINLKVFF NAYKTYLLCF HKGYGKAKLE CDMNTSDLL CVLELIDSSY WKSMSKVFLE QKVIKYILSQ DASLHRVKGC HSFKLWFLKR LNVAEFTVCP WVVNIDYHPT HMKAILTYID LVRMGLINI DRIHIKNKHK FNDEFYTSNL FYINYNFSDN THLLTKHIRI ANSELENNYN KLYHPTPETL ENILANPIKS N DKKTLNDY CIGKNVDSIM LPLLSNKKLI KSSAMIRTNY SKQDLYNLFP MVVIDRIIDH SGNTAKSNQL YTTTSHQISL VH NSTSLYC MLPWHHINRF NFVFSSTGCK ISIEYILKDL KIKDPNCIAF IGEGAGNLLL RTVVELHPDI RYIYRSLKDC NDH SLPIEF LRLYNGHINI DYGENLTIPA TDATNNIHWS YLHIKFAEPI SLFVCDAELS VTVNWSKIII EWSKHVRKCK YCSS VNKCM LIVKYHAQDD IDFKLDNITI LKTYVCLGSK LKGSEVYLVL TIGPANIFPV FNVVQNAKLI LSRTKNFIMP KKADK ESID ANIKSLIPFL CYPITKKGIN TALSKLKSVV SGDILSYSIA GRNEVFSNKL INHKHMNILK WFNHVLNFRS TELNYN HLY MVESTYPYLS ELLNSLTTNE LKKLIKITGS LLYNFHNE

UniProtKB: RNA-directed RNA polymerase L

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Macromolecule #2: Phosphoprotein

MacromoleculeName: Phosphoprotein / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: human respiratory syncytial virus
Molecular weightTheoretical: 29.032844 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MEKFAPEFHG EDANNRATKF LESIKGKFTS PKDPKKKDSI ISVNSIDIEV TKESPITSNS TIINPTNETD DTAGNKPNYQ RKPLVSFKE DPTPSDNPFS KLYKETIETF DNNEEESSYS YEEINDQTND NITARLDRID EKLSEILGML HTLVVASAGP T SARDGIRD ...String:
MEKFAPEFHG EDANNRATKF LESIKGKFTS PKDPKKKDSI ISVNSIDIEV TKESPITSNS TIINPTNETD DTAGNKPNYQ RKPLVSFKE DPTPSDNPFS KLYKETIETF DNNEEESSYS YEEINDQTND NITARLDRID EKLSEILGML HTLVVASAGP T SARDGIRD AMVGLREEMI EKIRTEALMT NDRLEAMARL RNEESEKMAK DTSDEVSLNP TSEKLNNLLE GNDSDNDLSL ED FKGENLY FQGHHHHHH

UniProtKB: Phosphoprotein

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Macromolecule #3: 5-(5-bromo-1-methyl-2-oxo-1,2-dihydrospiro[indole-3,4'-piperidin]...

MacromoleculeName: 5-(5-bromo-1-methyl-2-oxo-1,2-dihydrospiro[indole-3,4'-piperidin]-1'-yl)-3-chloropyridine-2-carbonitrile
type: ligand / ID: 3 / Number of copies: 1 / Formula: A1BVR
Molecular weightTheoretical: 431.714 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 1.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: DIFFRACTION / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.6 µm

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6pzk

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.72 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 1546578
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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