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- EMDB-47927: CryoEM Structure Of Respiratory Syncytial Virus Polymerase in com... -

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Basic information

Entry
Database: EMDB / ID: EMD-47927
TitleCryoEM Structure Of Respiratory Syncytial Virus Polymerase in complex with Novel Non-Nucleoside Inhibitor Compound 16
Map dataCryoEM map of Respiratory Syncytial Virus Polymerase with Novel Non-Nucleoside Inhibitor compound 16
Sample
  • Complex: CryoEM map of Respiratory Syncytial Virus Polymerase with Novel Non-Nucleoside Inhibitor compound 16
    • Protein or peptide: RNA-directed RNA polymerase L
    • Protein or peptide: Phosphoprotein
    • Protein or peptide: Compound 16
  • Ligand: water
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 / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.79 Å
AuthorsYin Y / Tran MT / Yu X / Jonckers T / Carney C
Funding support United States, 1 items
OrganizationGrant numberCountry
Not funded United States
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, 2024-
Header (metadata) releaseSep 24, 2025-
Map releaseSep 24, 2025-
UpdateSep 24, 2025-
Current statusSep 24, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_47927.png

Downloads & links

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Map

FileDownload / File: emd_47927.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryoEM map of Respiratory Syncytial Virus Polymerase with Novel Non-Nucleoside Inhibitor compound 16
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)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.948 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.378
Minimum - Maximum-2.0640578 - 2.7709653
Average (Standard dev.)0.00016408943 (±0.07182312)
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: Half map A of Respiratory Syncytial Virus Polymerase...

Fileemd_47927_half_map_1.map
AnnotationHalf map A of Respiratory Syncytial Virus Polymerase with Novel Non-Nucleoside Inhibitor compound 16
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B of Respiratory Syncytial Virus Polymerase...

Fileemd_47927_half_map_2.map
AnnotationHalf map B of Respiratory Syncytial Virus Polymerase with Novel Non-Nucleoside Inhibitor compound 16
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 16
Components
  • Complex: CryoEM map of Respiratory Syncytial Virus Polymerase with Novel Non-Nucleoside Inhibitor compound 16
    • Protein or peptide: RNA-directed RNA polymerase L
    • Protein or peptide: Phosphoprotein
    • Protein or peptide: Compound 16
  • Ligand: water

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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 16
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3

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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
Details: MEKFAPEFHGEDANNRATKFLESIKGKFTSPKDPKKKDSIISVNSIDIEVTKESPITSNS TIINPTNETDDTAGNKPNYQRKPLVSFKEDPTPSDNPFSKLYKETIETFDNNEEESSYSY EEINDQTNDNITARLDRIDEKLSEILGMLHTLVVASAGPTSARDGIRDAMVGLREEMIEK ...Details: MEKFAPEFHGEDANNRATKFLESIKGKFTSPKDPKKKDSIISVNSIDIEVTKESPITSNS TIINPTNETDDTAGNKPNYQRKPLVSFKEDPTPSDNPFSKLYKETIETFDNNEEESSYSY EEINDQTNDNITARLDRIDEKLSEILGMLHTLVVASAGPTSARDGIRDAMVGLREEMIEK IRTEALMTNDRLEAMARLRNEESEKMAKDTSDEVSLNPTSEKLNNLLEGNDSDNDLSLED FKGENLYFQGHHHHHH
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: Compound 16

MacromoleculeName: Compound 16 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 513.072 Da
SequenceString:
(A1BIT)(HPE)(A1BIY)

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Macromolecule #4: water

MacromoleculeName: water / type: ligand / ID: 4 / Number of copies: 4 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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: 2.2 µm / Nominal defocus min: 0.8 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: 2.79 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 1127112
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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