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- PDB-23ps: CryoEM structure of EV-D68 US/KY/14-18953 in complex with MFSD6-L3 -

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Basic information

Entry
Database: PDB / ID: 23ps
TitleCryoEM structure of EV-D68 US/KY/14-18953 in complex with MFSD6-L3
Components
  • (Capsid protein ...) x 4
  • Major facilitator superfamily domain-containing protein 6
KeywordsVIRAL PROTEIN / EV-D68 / MFSD6
Function / homology
Function and homology information


symbiont-mediated suppression of cytoplasmic pattern recognition receptor signaling pathway / antigen processing and presentation of exogenous peptide antigen via MHC class I / host cell mitochondrion / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MDA-5 activity / picornain 2A / symbiont-mediated suppression of host mRNA export from nucleus / symbiont genome entry into host cell via pore formation in plasma membrane / picornain 3C / T=pseudo3 icosahedral viral capsid / protein sequestering activity ...symbiont-mediated suppression of cytoplasmic pattern recognition receptor signaling pathway / antigen processing and presentation of exogenous peptide antigen via MHC class I / host cell mitochondrion / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MDA-5 activity / picornain 2A / symbiont-mediated suppression of host mRNA export from nucleus / symbiont genome entry into host cell via pore formation in plasma membrane / picornain 3C / T=pseudo3 icosahedral viral capsid / protein sequestering activity / host cell cytoplasmic vesicle membrane / ribonucleoside triphosphate phosphatase activity / nucleoside-triphosphate phosphatase / channel activity / monoatomic ion transmembrane transport / symbiont-mediated suppression of host toll-like receptor signaling pathway / symbiont-mediated suppression of host NF-kappaB cascade / RNA helicase activity / symbiont-mediated suppression of host innate immune response / endocytosis involved in viral entry into host cell / symbiont-mediated activation of host autophagy / RNA-directed RNA polymerase / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / virion attachment to host cell / host cell nucleus / structural molecule activity / proteolysis / DNA-templated transcription / RNA binding / zinc ion binding / ATP binding / membrane / plasma membrane / cytoplasm
Similarity search - Function
Major facilitator superfamily associated domain / : / MFS_1 like family / MFS transporter superfamily / : / Picornavirus coat protein / Poliovirus 3A protein-like / Poliovirus 3A protein like / Picornavirus 2B protein / Poliovirus core protein 3a, soluble domain ...Major facilitator superfamily associated domain / : / MFS_1 like family / MFS transporter superfamily / : / Picornavirus coat protein / Poliovirus 3A protein-like / Poliovirus 3A protein like / Picornavirus 2B protein / Poliovirus core protein 3a, soluble domain / Picornavirus 2B protein / Peptidase C3, picornavirus core protein 2A / Picornavirus core protein 2A / Picornavirus coat protein VP4 / Picornavirus coat protein (VP4) / Peptidase C3A/C3B, picornaviral / 3C cysteine protease (picornain 3C) / Picornavirales 3C/3C-like protease domain / Picornavirales 3C/3C-like protease domain profile. / Picornavirus capsid / picornavirus capsid protein / Helicase, superfamily 3, single-stranded RNA virus / Superfamily 3 helicase of positive ssRNA viruses domain profile. / Helicase, superfamily 3, single-stranded DNA/RNA virus / RNA helicase / Picornavirus/Calicivirus coat protein / Viral coat protein subunit / Reverse transcriptase/Diguanylate cyclase domain / RNA-directed RNA polymerase, C-terminal domain / Viral RNA-dependent RNA polymerase / RdRp of positive ssRNA viruses catalytic domain profile. / RNA-directed RNA polymerase, catalytic domain / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Genome polyprotein / Genome polyprotein / Genome polyprotein / Major facilitator superfamily domain-containing protein 6
Similarity search - Component
Biological speciesenterovirus D68
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.65 Å
AuthorsLiang, S.J. / Lou, Z.Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Commun / Year: 2026
Title: A dual-receptor checkpoint primes enterovirus D68 for respiratory cell entry.
Authors: Shengjian Liang / Haoran Guo / Zhili Xu / Zan Liu / Wanying Yang / Xiaoke Liu / Zhenyu Wei / Jichao Hou / Wei Huang / Wei Wang / Jiachen Li / Wendong Ma / Zhikang Deng / Haocong Qian / Yaxin ...Authors: Shengjian Liang / Haoran Guo / Zhili Xu / Zan Liu / Wanying Yang / Xiaoke Liu / Zhenyu Wei / Jichao Hou / Wei Huang / Wei Wang / Jiachen Li / Wendong Ma / Zhikang Deng / Haocong Qian / Yaxin Wang / Jialin Liu / Zihe Rao / Wei Wei / Zhiyong Lou /
Abstract: MFSD6 is a newly identified receptor that mediates the invasion of respiratory cells by enterovirus D68 (EV-D68), a non-polio enterovirus that causes severe respiratory disease and poliomyelitis-like ...MFSD6 is a newly identified receptor that mediates the invasion of respiratory cells by enterovirus D68 (EV-D68), a non-polio enterovirus that causes severe respiratory disease and poliomyelitis-like illness in children. Here, we report near-atomic-resolution cryo-electron microscopy (cryo-EM) structures of historical and contemporary AFM-associated EV-D68 strains, together with their complexes bound to the third extracellular loop of MFSD6 (MFSD6-L3). These structures uncover a previously unrecognized "binary gating switch" mechanism of virus-receptor engagement that differs from the reported model. In this mechanism, the N200-V208 segment of MFSD6, carrying a glycosylated Asn207, inserts into one capsomer, whereas the sialyl-Gal-terminated glycan of MFSD6 engages an adjacent capsomer. Neu5Ac binding induces conformational rearrangements that expel the pocket factor, destabilize the virion, and prime infection. Functional analyses further define the contributions of the receptor-contacting residues and glycans to viral attachment and entry. Together, our findings refine the molecular basis of EV-D68 recognition of MFSD6 and reveal a glycan-mediated dual-lock mechanism that may enhance receptor specificity, prevent premature uncoating, and ensure productive infection only upon engagement of the correct host receptor. These results provide broader insight into enterovirus tropism and establish a framework for structure-guided antiviral design.
History
DepositionFeb 12, 2026Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Sep 9, 2026Provider: repository / Type: Initial release
Revision 1.0Sep 9, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
B: Capsid protein VP2
C: Capsid protein VP3
D: Capsid protein VP4
A: Capsid protein VP1
E: Major facilitator superfamily domain-containing protein 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)107,3367
Polymers105,6055
Non-polymers1,7322
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Capsid protein ... , 4 types, 4 molecules BCDA

#1: Protein Capsid protein VP2


Mass: 26630.186 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) enterovirus D68 / Production host: Homo sapiens (human)
References: UniProt: A0A097BW19, picornain 2A, nucleoside-triphosphate phosphatase, picornain 3C, RNA-directed RNA polymerase
#2: Protein Capsid protein VP3


Mass: 27282.035 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) enterovirus D68 / Production host: Homo sapiens (human)
References: UniProt: A0A097BW19, picornain 2A, nucleoside-triphosphate phosphatase, picornain 3C, RNA-directed RNA polymerase
#3: Protein/peptide Capsid protein VP4 / P1A / Virion protein 4


Mass: 4210.649 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) enterovirus D68 / Production host: Homo sapiens (human) / References: UniProt: Q68T42
#4: Protein Capsid protein VP1


Mass: 32858.281 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) enterovirus D68 / Production host: Homo sapiens (human)
References: UniProt: A0A8D5ZMD3, picornain 2A, nucleoside-triphosphate phosphatase, picornain 3C, RNA-directed RNA polymerase

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Protein , 1 types, 1 molecules E

#5: Protein Major facilitator superfamily domain-containing protein 6 / Macrophage MHC class I receptor 2 homolog


Mass: 14623.599 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MFSD6, MMR2 / Production host: Homo sapiens (human) / References: UniProt: Q6ZSS7

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Sugars , 2 types, 2 molecules

#6: Polysaccharide alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2- ...alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 1056.964 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3[DManpa1-6]DManpb1-4DGlcpNAcb1-4[LFucpa1-6]DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/4,6,5/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5][a1221m-1a_1-5]/1-1-2-3-3-4/a4-b1_a6-f1_b4-c1_c3-d1_c6-e1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{}}}[(6+1)][a-L-Fucp]{}}LINUCSPDB-CARE
#7: Polysaccharide N-acetyl-alpha-neuraminic acid-(2-6)-beta-D-galactopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 674.604 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DNeup5Aca2-6DGalpb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,3,2/[a2122h-1b_1-5_2*NCC/3=O][a2112h-1b_1-5][Aad21122h-2a_2-6_5*NCC/3=O]/1-2-3/a4-b1_b6-c2WURCSPDB2Glycan 1.1.0
[][b-D-GlcpNAc]{[(4+1)][b-D-Galp]{[(6+2)][a-D-Neup5Ac]{}}}LINUCSPDB-CARE

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Details

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: enterovirus D68 / Type: VIRUS / Entity ID: #4, #1-#3, #5 / Source: NATURAL
Source (natural)Organism: enterovirus D68
Details of virusEmpty: NO / Enveloped: NO / Isolate: STRAIN / Type: VIRION
Buffer solutionpH: 7.4
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: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
2PHENIXmodel refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.65 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 73080 / Symmetry type: POINT
RefinementHighest resolution: 2.65 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0046573
ELECTRON MICROSCOPYf_angle_d0.4968952
ELECTRON MICROSCOPYf_dihedral_angle_d7.455890
ELECTRON MICROSCOPYf_chiral_restr0.0431007
ELECTRON MICROSCOPYf_plane_restr0.0041155

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