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- PDB-9vul: Cryo-EM structure of the human measles virus RNA-dependent RNA po... -

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Basic information

Entry
Database: PDB / ID: 9vul
TitleCryo-EM structure of the human measles virus RNA-dependent RNA polymerase bound to allosteric inhibitor ERDRP-0519
Components
  • Maltose/maltodextrin-binding periplasmic protein,Phosphoprotein
  • Maltose/maltodextrin-binding periplasmic protein,RNA-directed RNA polymerase L,Strep II and FLAG tag
KeywordsVIRAL PROTEIN / Measles virus RNA-dependent RNA polymerase complex bound to allosteric inhibitor ERDRP-0519
Function / homology
Function and homology information


GDP polyribonucleotidyltransferase / 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 ...GDP polyribonucleotidyltransferase / 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 / viral genome replication / cell chemotaxis / virion component / outer membrane-bounded periplasmic space / host cell cytoplasm / periplasmic space / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / RNA-directed RNA polymerase / RNA-directed RNA polymerase activity / GTPase activity / DNA damage response / DNA-templated transcription / RNA binding / ATP binding / membrane
Similarity search - Function
RNA polymerase, phosphoprotein P, C-terminal XD, paramyxovirinae / 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 ...RNA polymerase, phosphoprotein P, C-terminal XD, paramyxovirinae / 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 / S-adenosyl-L-methionine-dependent methyltransferase superfamily
Similarity search - Domain/homology
: / Maltose/maltodextrin-binding periplasmic protein / Phosphoprotein / RNA-directed RNA polymerase L
Similarity search - Component
Biological speciesEscherichia coli K-12 (bacteria)
Measles virus genotype A-vaccine
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.13 Å
AuthorsDu, T. / Wang, J. / Wu, S. / Ru, H.
Funding support China, 1items
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, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0May 27, 2026Provider: repository / Type: Initial release
Revision 1.0May 27, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0May 27, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0May 27, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0May 27, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0May 27, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0May 27, 2026Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0May 27, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Maltose/maltodextrin-binding periplasmic protein,Phosphoprotein
B: Maltose/maltodextrin-binding periplasmic protein,Phosphoprotein
C: Maltose/maltodextrin-binding periplasmic protein,Phosphoprotein
D: Maltose/maltodextrin-binding periplasmic protein,Phosphoprotein
L: Maltose/maltodextrin-binding periplasmic protein,RNA-directed RNA polymerase L,Strep II and FLAG tag
hetero molecules


Theoretical massNumber of molelcules
Total (without water)563,0058
Polymers562,3445
Non-polymers6603
Water00
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
Maltose/maltodextrin-binding periplasmic protein,Phosphoprotein / MMBP / Maltodextrin-binding protein / Maltose-binding protein / MBP / Protein P


Mass: 66334.383 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Details: N-terminal MBP tag, 3C cleavage site; Sequence reference for Measles virus genotype A-vaccine is not available at the time of biocuration. Current sequence reference is from UniProt id P35974.
Source: (gene. exp.) Escherichia coli K-12 (bacteria), (gene. exp.) Measles virus genotype A-vaccine
Strain: K-12 / Gene: malE, b4034, JW3994, P/V / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P0AEX9, UniProt: P35974
#2: Protein Maltose/maltodextrin-binding periplasmic protein,RNA-directed RNA polymerase L,Strep II and FLAG tag / MMBP / Maltodextrin-binding protein / Maltose-binding protein / MBP / Protein L / Large structural ...MMBP / Maltodextrin-binding protein / Maltose-binding protein / MBP / Protein L / Large structural protein / Replicase / Transcriptase


Mass: 297006.906 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: N-terminal HisMBP tag, 3C cleavage site, TEV cleavage site, C-terminal Strep II and FLAG tag; Sequence reference for Measles virus genotype A-vaccine is not available at the time of ...Details: N-terminal HisMBP tag, 3C cleavage site, TEV cleavage site, C-terminal Strep II and FLAG tag; Sequence reference for Measles virus genotype A-vaccine is not available at the time of biocuration. Current sequence reference is from UniProt id P35975.
Source: (gene. exp.) Escherichia coli K-12 (bacteria), (gene. exp.) Measles virus genotype A-vaccine, (gene. exp.) synthetic construct (others)
Strain: K-12 / Gene: malE, b4034, JW3994 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P0AEX9, UniProt: P35975, RNA-directed RNA polymerase, Hydrolases; Acting on acid anhydrides; In phosphorus-containing anhydrides, GDP polyribonucleotidyltransferase, NNS virus cap methyltransferase
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-A1EF9 / 2-methyl-~{N}-[4-[(2~{S})-2-(2-morpholin-4-ylethyl)piperidin-1-yl]sulfonylphenyl]-5-(trifluoromethyl)pyrazole-3-carboxamide


Mass: 529.576 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H30F3N5O4S / 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: Measles virus RNA-dependent RNA polymerase complex bound to allosteric inhibitor ERDRP-0519
Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightValue: 0.56 MDa / Experimental value: NO
Source (natural)Organism: Measles virus genotype A-vaccine
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5 / Details: 300mM NaCl, 25mM HEPES, 1mM TCEP, 6mM MgCl2
SpecimenConc.: 1.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: This sample was monodisperse.
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: BRIGHT FIELD / Nominal defocus max: 1500 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 52.52 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
4cryoSPARCCTF correction
10cryoSPARCinitial Euler assignment
11cryoSPARCfinal Euler assignment
12cryoSPARCclassification
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.13 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 177478 / Symmetry type: POINT
RefinementHighest resolution: 3.13 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00312450
ELECTRON MICROSCOPYf_angle_d0.58516843
ELECTRON MICROSCOPYf_dihedral_angle_d5.2471688
ELECTRON MICROSCOPYf_chiral_restr0.0411914
ELECTRON MICROSCOPYf_plane_restr0.0042128

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