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- EMDB-65368: Cryo-EM structure of the Nipah virus RNA-dependent RNA polymerase... -

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Entry
Database: EMDB / ID: EMD-65368
TitleCryo-EM structure of the Nipah virus RNA-dependent RNA polymerase complex bound to allosteric inhibitor ERDRP-0519
Map dataAuthor stated: The model was refined by phenix.refine and I used the artificial structural factor file which was converted from the map through phenix.map_to_structural_factors program to do the refinement. So it is not a crystal structure.
Sample
  • Complex: Nipah virus RNA-dependent RNA polymerase complex bound to allosteric inhibitor ERDRP-0519
    • Protein or peptide: Maltose/maltodextrin-binding periplasmic protein,RNA-directed RNA polymerase L
    • Protein or peptide: Maltose/maltodextrin-binding periplasmic protein,Phosphoprotein
  • Ligand: ZINC ION
  • Ligand: 2-methyl-~{N}-[4-[(2~{S})-2-(2-morpholin-4-ylethyl)piperidin-1-yl]sulfonylphenyl]-5-(trifluoromethyl)pyrazole-3-carboxamide
  • Ligand: water
KeywordsRNA-dependent RNA polymerase complex bound to allosteric inhibitor ERDRP-0519 / VIRAL PROTEIN
Function / homology
Function and homology information


negative stranded viral RNA transcription / GDP polyribonucleotidyltransferase / negative stranded viral RNA replication / detection of maltose stimulus / maltose transport complex / carbohydrate transport / carbohydrate transmembrane transporter activity / maltose binding / maltose transport / maltodextrin transmembrane transport ...negative stranded viral RNA transcription / GDP polyribonucleotidyltransferase / negative stranded viral RNA replication / detection of maltose stimulus / maltose transport complex / carbohydrate transport / carbohydrate transmembrane transporter activity / maltose binding / maltose transport / maltodextrin transmembrane transport / Hydrolases; Acting on acid anhydrides; In phosphorus-containing anhydrides / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / ATP-binding cassette (ABC) transporter complex / cell chemotaxis / virion component / outer membrane-bounded periplasmic space / molecular adaptor activity / host cell cytoplasm / periplasmic space / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / symbiont-mediated suppression of host innate immune response / RNA-directed RNA polymerase / RNA-directed RNA polymerase activity / GTPase activity / DNA damage response / ATP binding / membrane
Similarity search - Function
Phosphoprotein P region PNT disordered / Phosphoprotein P region PNT disordered / Phosphoprotein P soyouz module / N-terminal region of Paramyxovirinae phosphoprotein (P) / Paramyxovirus structural protein P/V, N-terminal domain / Paramyxovirus structural protein V/P N-terminus / RNA-directed RNA polymerase, paramyxovirus / P/V phosphoprotein, paramyxoviral / Paramyxovirus P/V phosphoprotein C-terminal / Mononegavirus L protein 2-O-ribose methyltransferase ...Phosphoprotein P region PNT disordered / Phosphoprotein P region PNT disordered / Phosphoprotein P soyouz module / N-terminal region of Paramyxovirinae phosphoprotein (P) / Paramyxovirus structural protein P/V, N-terminal domain / Paramyxovirus structural protein V/P N-terminus / RNA-directed RNA polymerase, paramyxovirus / P/V phosphoprotein, paramyxoviral / Paramyxovirus P/V phosphoprotein C-terminal / 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. / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / Bacterial extracellular solute-binding protein / Bacterial extracellular solute-binding protein / Ribosomal RNA methyltransferase, FtsJ domain / FtsJ-like methyltransferase
Similarity search - Domain/homology
Maltose/maltodextrin-binding periplasmic protein / RNA-directed RNA polymerase L / Phosphoprotein
Similarity search - Component
Biological speciesNipah virus / Henipavirus nipahense
Methodsingle particle reconstruction / cryo EM / Resolution: 2.84 Å
AuthorsDu T / Wang J / Wu S / Ru H
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32371344 China
CitationJournal: Proc Natl Acad Sci U S A / Year: 2026
Title: Structural insights into measles virus RNA synthesis regulation and pan-paramyxoviral polymerase inhibition by ERDRP-0519.
Authors: Tianjiao Du / Jiening Wang / Chengji Yang / Rubing Xue / Ying Chen / Kaiyue Jie / Xiaokang Zhang / Long Zhang / Gaojie Song / Qiansen Zhang / Shan Wu / Heng Ru /
Abstract: Nonsegmented negative-sense RNA viruses (nsNSVs) rely on a multifunctional RNA-dependent RNA polymerase (RdRP) complex for transcription and replication. In measles virus (MeV), the nonstructural ...Nonsegmented negative-sense RNA viruses (nsNSVs) rely on a multifunctional RNA-dependent RNA polymerase (RdRP) complex for transcription and replication. In measles virus (MeV), the nonstructural protein C has long been implicated in regulating RNA synthesis, yet its precise role remains unclear. Here, we show that the MeV C protein directly associates with the RdRP complex. Using cryoelectron microscopy, we determined atomic-resolution structures of the MeV polymerase with and without C, revealing that C binding stabilizes the C-terminal region of L and locks the complex into a replication-competent elongation state. Biochemical data further show that C promotes N protein recruitment, enhancing polymerase processivity through facilitating encapsidation during replication. Additionally, we also resolved high-resolution structures of MeV and Nipah virus (NiV) polymerases bound to ERDRP-0519, an orally available morbillivirus inhibitor. Unexpectedly, the compound occupies an allosteric pocket within the RdRp domain rather than the previously predicted PRNTase domain, overlapping conserved resistance sites. This binding induces conformational changes in palm subdomain, blocking RNA template and nucleotide engagement, thereby halting RNA synthesis. These findings uncover distinct regulatory and inhibitory mechanisms in paramyxovirus polymerases and provide a structural framework for the rational design of broad-spectrum antivirals targeting MeV, NiV, and potentially other clinically relevant nsNSVs.
History
DepositionJul 13, 2025-
Header (metadata) releaseMay 27, 2026-
Map releaseMay 27, 2026-
UpdateMay 27, 2026-
Current statusMay 27, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_65368.png

Downloads & links

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Map

FileDownload / File: emd_65368.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationAuthor stated: The model was refined by phenix.refine and I used the artificial structural factor file which was converted from the map through phenix.map_to_structural_factors program to do the refinement. So it is not a crystal structure.
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.93 Å/pix.
x 360 pix.
= 334.8 Å		0.93 Å/pix.
x 360 pix.
= 334.8 Å		0.93 Å/pix.
x 360 pix.
= 334.8 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.93 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.48
Minimum - Maximum-2.8866837 - 4.856144
Average (Standard dev.)-0.00007929813 (±0.08435874)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 334.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_65368_msk_1.map
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Half map: #2

Fileemd_65368_half_map_1.map
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Half map: #1

Fileemd_65368_half_map_2.map
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Sample components

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Entire : Nipah virus RNA-dependent RNA polymerase complex bound to alloste...

EntireName: Nipah virus RNA-dependent RNA polymerase complex bound to allosteric inhibitor ERDRP-0519
Components
  • Complex: Nipah virus RNA-dependent RNA polymerase complex bound to allosteric inhibitor ERDRP-0519
    • Protein or peptide: Maltose/maltodextrin-binding periplasmic protein,RNA-directed RNA polymerase L
    • Protein or peptide: Maltose/maltodextrin-binding periplasmic protein,Phosphoprotein
  • Ligand: ZINC ION
  • Ligand: 2-methyl-~{N}-[4-[(2~{S})-2-(2-morpholin-4-ylethyl)piperidin-1-yl]sulfonylphenyl]-5-(trifluoromethyl)pyrazole-3-carboxamide
  • Ligand: water

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Supramolecule #1: Nipah virus RNA-dependent RNA polymerase complex bound to alloste...

SupramoleculeName: Nipah virus RNA-dependent RNA polymerase complex bound to allosteric inhibitor ERDRP-0519
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Nipah virus
Molecular weightTheoretical: 500 KDa

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Macromolecule #1: Maltose/maltodextrin-binding periplasmic protein,RNA-directed RNA...

MacromoleculeName: Maltose/maltodextrin-binding periplasmic protein,RNA-directed RNA polymerase L
type: protein_or_peptide / ID: 1
Details: N-terminal Strep II and HisMBP tag, 3C cleavage site
Number of copies: 1 / Enantiomer: LEVO / EC number: RNA-directed RNA polymerase
Source (natural)Organism: Henipavirus nipahense
Molecular weightTheoretical: 215.827828 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGSGWSHPQF EKGGGSGGGS GGSAWSHPQF EKGSASHHHH HHGTKTEEGK LVIWINGDKG YNGLAEVGKK FEKDTGIKVT VEHPDKLEE KFPQVAATGD GPDIIFWAHD RFGGYAQSGL LAEITPDKAF QDKLYPFTWD AVRYNGKLIA YPIAVEALSL I YNKDLLPN ...String:
MGSGWSHPQF EKGGGSGGGS GGSAWSHPQF EKGSASHHHH HHGTKTEEGK LVIWINGDKG YNGLAEVGKK FEKDTGIKVT VEHPDKLEE KFPQVAATGD GPDIIFWAHD RFGGYAQSGL LAEITPDKAF QDKLYPFTWD AVRYNGKLIA YPIAVEALSL I YNKDLLPN PPKTWEEIPA LDKELKAKGK SALMFNLQEP YFTWPLIAAD GGYAFKYENG KYDIKDVGVD NAGAKAGLTF LV DLIKNKH MNADTDYSIA EAAFNKGETA MTINGPWAWS NIDTSKVNYG VTVLPTFKGQ PSKPFVGVLS AGINAASPNK ELA KEFLEN YLLTDEGLEA VNKDKPLGAV ALKSYEEELA KDPRIAATME NAQKGEIMPN IPQMSAFWYA VRTAVINAAS GRQT VDEAL KDAQTGTDYD IPTTLEVLFQ GPGSMADELS ISDIIYPECH LDSPIVSGKL ISAIEYAQLR HNQPSDDKRL SENIR LNLH GKRKSLYILR QSKQGDYIRN NIKNLKEFMH IAYPECNNIL FSITSQGMTS KLDNIMKKSF KAYNIISKKV IGMLQN ITR NLITQDRRDE IINIHECRRL GDLGKNMSQS KWYECFLFWF TIKTEMRAVI KNSQKPKFRS DSCIIHMRDK STEIILN PN LICIFKSDKT GKKCYYLTPE MVLMYCDVLE GRMMMETTVK SDIKYQPLIS RSNALWGLID PLFPVMGNRI YNIVSMIE P LVLALLQLKD EARILRGAFL HHCIKEMHQE LSECGFTDQK IRSMFIDDLL SILNIDNIHL LAEFFSFFRT FGHPILEAK VAAEKVREHM LADKVLEYAP IMKAHAIFCG TIINGYRDRH GGAWPPLYLP AHASKHIIRL KNSGESLTID DCVKNWESFC GIQFDCFME LKLDSDLSMY MKDKALSPIK DEWDSVYPRE VLSYTPPKST EPRRLVDVFV NDENFDPYNM LEYVLSGAYL E DEQFNVSY SLKEKETKQA GRLFAKMTYK MRACQVIAEA LIASGVGKYF KENGMVKDEH ELLKTLFQLS ISSVPRGNSQ GN DPQSINN IERDFQYFKG VTTNVKDKKN NSFNKVKSAL NNPCQADGVH HNMSPNTRNR YKCSNTSKSF LDYHTEFNPH NHY KSDNTE AAVLSRYEDN TGTKFDTVSA FLTTDLKKFC LNWRYESMAI FAERLDEIYG LPGFFNWMHK RLERSVIYVA DPNC PPNID KHMELEKTPE DDIFIHYPKG GIEGYSQKTW TIATIPFLFL SAYETNTRIA AIVQGDNESI AITQKVHPNL PYKVK KEIC AKQAQLYFER LRMNLRALGH NLKATETIIS THLFIYSKKI HYDGAVLSQA LKSMSRCCFW SETLVDETRS ACSNIS TTI AKAIENGLSR NVGYCINILK VIQQLLISTE FSINETLTLD VTSPISNNLD WLITAALIPA PIGGFNYLNL SRIFVRN IG DPVTASLADL KRMIDHSIMT ESVLQKVMNQ EPGDASFLDW ASDPYSGNLP DSQSITKTIK NITARTILRN SPNPMLKG L FHDKSFDEDL ELASFLMDRR VILPRAAHEI LDNSLTGARE EIAGLLDTTK GLIRSGLRKS GLQPKLVSRL SHHDYNQFL ILNKLLSNRR QNDLISSNTC SVDLARALRS HMWRELALGR VIYGLEVPDA LEAMVGRYIT GSLECQICEQ GNTMYGWFFV PRDSQLDQV DREHSSIRVP YVGSSTDERS DIKLGNVKRP TKALRSAIRI ATVYTWAYGD NEECWYEAWY LASQRVNIDL D VLKAITPV STSNNLSHRL RDKSTQFKFA GSVLNRVSRY VNISNDNLDF RIEGEKVDTN LIYQQAMLLG LSVLEGKFRL RL ETDDYNG IYHLHVKDNC CVKEVADVGQ VDAELPIPEY TEVDNNHLIY DPDPVSESRD YKDDDDK

UniProtKB: Maltose/maltodextrin-binding periplasmic protein, RNA-directed RNA polymerase L

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Macromolecule #2: Maltose/maltodextrin-binding periplasmic protein,Phosphoprotein

MacromoleculeName: Maltose/maltodextrin-binding periplasmic protein,Phosphoprotein
type: protein_or_peptide / ID: 2
Details: N-terminal HisMBP tag, 3C cleavage site,N-terminal HisMBP tag, 3C cleavage site
Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Henipavirus nipahense
Molecular weightTheoretical: 70.995812 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGSSHHHHHH GTKTEEGKLV IWINGDKGYN GLAEVGKKFE KDTGIKVTVE HPDKLEEKFP QVAATGDGPD IIFWAHDRFG GYAQSGLLA EITPDKAFQD KLYPFTWDAV RYNGKLIAYP IAVEALSLIY NKDLLPNPPK TWEEIPALDK ELKAKGKSAL M FNLQEPYF ...String:
MGSSHHHHHH GTKTEEGKLV IWINGDKGYN GLAEVGKKFE KDTGIKVTVE HPDKLEEKFP QVAATGDGPD IIFWAHDRFG GYAQSGLLA EITPDKAFQD KLYPFTWDAV RYNGKLIAYP IAVEALSLIY NKDLLPNPPK TWEEIPALDK ELKAKGKSAL M FNLQEPYF TWPLIAADGG YAFKYENGKY DIKDVGVDNA GAKAGLTFLV DLIKNKHMNA DTDYSIAEAA FNKGETAMTI NG PWAWSNI DTSKVNYGVT VLPTFKGQPS KPFVGVLSAG INAASPNKEL AKEFLENYLL TDEGLEAVNK DKPLGAVALK SYE EELAKD PRIAATMENA QKGEIMPNIP QMSAFWYAVR TAVINAASGR QTVDEALKDA QTGTDYDIPT TLEVLFQGPL GSND SLDDK YIMPSDDFSN TFFPHDTDRL NYHADHLGDY DLETLCEESV LMGVINSIKL INLDMRLNHI EEQVKEIPKI INKLE SIDR VLAKTNTALS TIEGHLVSMM IMIPGKGKGE RKGKNNPELK PVIGRDILEQ QSLFSFDNVK NFRDGSLTNE PYGAAV QLR EDLILPELNF EETNASQFVP MADDSSRDVI KTLIRTHIKD RELRSELIGY LNKAENDEEI QEIANTVNDI IDGNI

UniProtKB: Maltose/maltodextrin-binding periplasmic protein, Phosphoprotein

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Macromolecule #3: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 3 / Number of copies: 2 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #4: 2-methyl-~{N}-[4-[(2~{S})-2-(2-morpholin-4-ylethyl)piperidin-1-yl...

MacromoleculeName: 2-methyl-~{N}-[4-[(2~{S})-2-(2-morpholin-4-ylethyl)piperidin-1-yl]sulfonylphenyl]-5-(trifluoromethyl)pyrazole-3-carboxamide
type: ligand / ID: 4 / Number of copies: 1 / Formula: A1EF9
Molecular weightTheoretical: 529.576 Da

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Macromolecule #5: water

MacromoleculeName: water / type: ligand / ID: 5 / Number of copies: 1 / 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

Concentration1.2 mg/mL
BufferpH: 7.5 / Details: 300mM NaCl, 25mM HEPES, 1mM TCEP, 6mM MgCl2
VitrificationCryogen name: ETHANE
DetailsThis sample was monodisperse.

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.84 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 158764
Initial angle assignmentType: PROJECTION MATCHING / Software - Name: cryoSPARC
Final angle assignmentType: PROJECTION MATCHING / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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