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- EMDB-43795: CryoEM structure of AMETA-A3 -

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Basic information

Entry
Database: EMDB / ID: EMD-43795
TitleCryoEM structure of AMETA-A3
Map data
Sample
  • Complex: Adaptive Multi-Epitope Targeting and Avidity-Enhanced (AMETA) Nanobody Platform
    • Protein or peptide: Isoform 1 of Immunoglobulin heavy constant mu
    • Protein or peptide: Immunoglobulin J chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsIgM / nanobody / IMMUNE SYSTEM
Function / homology
Function and homology information


hexameric IgM immunoglobulin complex / IgM B cell receptor complex / dimeric IgA immunoglobulin complex / secretory dimeric IgA immunoglobulin complex / pentameric IgM immunoglobulin complex / monomeric IgA immunoglobulin complex / secretory IgA immunoglobulin complex / IgA binding / pre-B cell allelic exclusion / IgM immunoglobulin complex ...hexameric IgM immunoglobulin complex / IgM B cell receptor complex / dimeric IgA immunoglobulin complex / secretory dimeric IgA immunoglobulin complex / pentameric IgM immunoglobulin complex / monomeric IgA immunoglobulin complex / secretory IgA immunoglobulin complex / IgA binding / pre-B cell allelic exclusion / IgM immunoglobulin complex / glomerular filtration / CD22 mediated BCR regulation / immunoglobulin receptor binding / positive regulation of respiratory burst / humoral immune response / Scavenging of heme from plasma / antigen binding / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / Cell surface interactions at the vascular wall / B cell receptor signaling pathway / antibacterial humoral response / protein-containing complex assembly / protein-macromolecule adaptor activity / defense response to Gram-negative bacterium / blood microparticle / adaptive immune response / Potential therapeutics for SARS / immune response / innate immune response / cell surface / protein homodimerization activity / extracellular space / extracellular exosome / extracellular region / plasma membrane
Similarity search - Function
Immunoglobulin J chain / Immunoglobulin J chain / : / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulins and major histocompatibility complex proteins signature. / Immunoglobulin C-Type / Immunoglobulin C1-set / Immunoglobulin C1-set domain / Ig-like domain profile. / Immunoglobulin-like domain ...Immunoglobulin J chain / Immunoglobulin J chain / : / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulins and major histocompatibility complex proteins signature. / Immunoglobulin C-Type / Immunoglobulin C1-set / Immunoglobulin C1-set domain / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Immunoglobulin J chain / Immunoglobulin heavy constant mu
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsHuang W / Sang Z / Taylor D
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM133841 United States
CitationJournal: Cell / Year: 2024
Title: Adaptive multi-epitope targeting and avidity-enhanced nanobody platform for ultrapotent, durable antiviral therapy.
Authors: Yufei Xiang / Jialu Xu / Briana L McGovern / Anna Ranzenigo / Wei Huang / Zhe Sang / Juan Shen / Randy Diaz-Tapia / Ngoc Dung Pham / Abraham J P Teunissen / M Luis Rodriguez / Jared Benjamin ...Authors: Yufei Xiang / Jialu Xu / Briana L McGovern / Anna Ranzenigo / Wei Huang / Zhe Sang / Juan Shen / Randy Diaz-Tapia / Ngoc Dung Pham / Abraham J P Teunissen / M Luis Rodriguez / Jared Benjamin / Derek J Taylor / Mandy M T van Leent / Kris M White / Adolfo García-Sastre / Peijun Zhang / Yi Shi /
Abstract: Pathogens constantly evolve and can develop mutations that evade host immunity and treatment. Addressing these escape mechanisms requires targeting evolutionarily conserved vulnerabilities, as ...Pathogens constantly evolve and can develop mutations that evade host immunity and treatment. Addressing these escape mechanisms requires targeting evolutionarily conserved vulnerabilities, as mutations in these regions often impose fitness costs. We introduce adaptive multi-epitope targeting with enhanced avidity (AMETA), a modular and multivalent nanobody platform that conjugates potent bispecific nanobodies to a human immunoglobulin M (IgM) scaffold. AMETA can display 20+ nanobodies, enabling superior avidity binding to multiple conserved and neutralizing epitopes. By leveraging multi-epitope SARS-CoV-2 nanobodies and structure-guided design, AMETA constructs exponentially enhance antiviral potency, surpassing monomeric nanobodies by over a million-fold. These constructs demonstrate ultrapotent, broad, and durable efficacy against pathogenic sarbecoviruses, including Omicron sublineages, with robust preclinical results. Structural analysis through cryoelectron microscopy and modeling has uncovered multiple antiviral mechanisms within a single construct. At picomolar to nanomolar concentrations, AMETA efficiently induces inter-spike and inter-virus cross-linking, promoting spike post-fusion and striking viral disarmament. AMETA's modularity enables rapid, cost-effective production and adaptation to evolving pathogens.
History
DepositionFeb 23, 2024-
Header (metadata) releaseNov 6, 2024-
Map releaseNov 6, 2024-
UpdateDec 11, 2024-
Current statusDec 11, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43795.png

Downloads & links

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Map

FileDownload / File: emd_43795.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.34 Å/pix.
x 360 pix.
= 480.96 Å		1.34 Å/pix.
x 360 pix.
= 480.96 Å		1.34 Å/pix.
x 360 pix.
= 480.96 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.336 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.42750067 - 1.1630119
Average (Standard dev.)-0.000014534355 (±0.018678684)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 480.96 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_43795_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_43795_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : Adaptive Multi-Epitope Targeting and Avidity-Enhanced (AMETA) Nan...

EntireName: Adaptive Multi-Epitope Targeting and Avidity-Enhanced (AMETA) Nanobody Platform
Components
  • Complex: Adaptive Multi-Epitope Targeting and Avidity-Enhanced (AMETA) Nanobody Platform
    • Protein or peptide: Isoform 1 of Immunoglobulin heavy constant mu
    • Protein or peptide: Immunoglobulin J chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Adaptive Multi-Epitope Targeting and Avidity-Enhanced (AMETA) Nan...

SupramoleculeName: Adaptive Multi-Epitope Targeting and Avidity-Enhanced (AMETA) Nanobody Platform
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Isoform 1 of Immunoglobulin heavy constant mu

MacromoleculeName: Isoform 1 of Immunoglobulin heavy constant mu / type: protein_or_peptide / ID: 1 / Number of copies: 10 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.152266 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GSRGVPHIVM VDAYKRYKGG GGSIDTTIAE LPPKVSVFVP PRDGFFGNPR KSKLICQATG FSPRQIQVSW LREGKQVGSG VTTDQVQAE AKESGPTTYK VTSTLTIKES DWLGQSMFTC RVDHRGLTFQ QNASSMCVPD QDTAIRVFAI PPSFASIFLT K STKLTCLV ...String:
GSRGVPHIVM VDAYKRYKGG GGSIDTTIAE LPPKVSVFVP PRDGFFGNPR KSKLICQATG FSPRQIQVSW LREGKQVGSG VTTDQVQAE AKESGPTTYK VTSTLTIKES DWLGQSMFTC RVDHRGLTFQ QNASSMCVPD QDTAIRVFAI PPSFASIFLT K STKLTCLV TDLTTYDSVT ISWTRQNGEA VKTHTNISES HPNATFSAVG EASICEDDWN SGERFTCTVT HTDLPSPLKQ TI SRPKGVA LHRPDVYLLP PAREQLNLRE SATITCLVTG FSPADVFVQW MQRGQPLSPE KYVTSAPMPE PQAPGRYFAH SIL TVSEEE WNTGETYTCV VAHEALPNRV TERTVDKSTG KPTLYNVSLV MSDTAGTCY

UniProtKB: Immunoglobulin heavy constant mu

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Macromolecule #2: Immunoglobulin J chain

MacromoleculeName: Immunoglobulin J chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 19.225762 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MKNHLLFWGV LAVFIKAVHV KAQEDERIVL VDNKCKCARI TSRIIRSSED PNEDIVERNI RIIVPLNNRE NISDPTSPLR TRFVYHLSD LCKKCDPTEV ELDNQIVTAT QSNICDEDSA TETCYTYDRN KCYTAVVPLV YGGETKMVET ALTPDACYPD H HHHHHHH

UniProtKB: Immunoglobulin J chain

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Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 5 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOCONTINUUM (6k x 4k) / Average electron dose: 34.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 233181
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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