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- EMDB-61732: Cryo-EM structure of the HMBPP-primed BTN3A1-BTN3A2-BTN2A1 in com... -

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Basic information

Entry
Database: EMDB / ID: EMD-61732
TitleCryo-EM structure of the HMBPP-primed BTN3A1-BTN3A2-BTN2A1 in complex with agonist antibody TH001
Map dataEMReady
Sample
  • Complex: HMBPP-primed BTN3A1-BTN3A2-BTN2A1 in complex with agonist antibody TH001
    • Protein or peptide: Butyrophilin subfamily 3 member A1
    • Protein or peptide: Butyrophilin subfamily 3 member A2
    • Protein or peptide: Butyrophilin subfamily 2 member A1
    • Protein or peptide: BTN3A agonist antibody TH001, variable domain of light chain
    • Protein or peptide: BTN3A agonist antibody TH001, variable domain of heavy chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Keywordsantibody / agonist / phosphoantigen / butyrophilin / IMMUNE SYSTEM
Function / homology
Function and homology information


Butyrophilin (BTN) family interactions / T cell mediated immunity / activated T cell proliferation / regulation of cytokine production / positive regulation of cytokine production / lipid metabolic process / positive regulation of type II interferon production / T cell receptor signaling pathway / adaptive immune response / signaling receptor binding ...Butyrophilin (BTN) family interactions / T cell mediated immunity / activated T cell proliferation / regulation of cytokine production / positive regulation of cytokine production / lipid metabolic process / positive regulation of type II interferon production / T cell receptor signaling pathway / adaptive immune response / signaling receptor binding / external side of plasma membrane / membrane / plasma membrane
Similarity search - Function
Butyrophilin subfamily 1/2, SPRY/PRY domain / Butyrophilin subfamily 3, PRY/SPRY domain / : / : / Butyrophilin subfamily 3 member A2-like, Ig-C domain / SPRY-associated domain / SPRY-associated / PRY / Butyrophylin-like, SPRY domain / SPRY domain ...Butyrophilin subfamily 1/2, SPRY/PRY domain / Butyrophilin subfamily 3, PRY/SPRY domain / : / : / Butyrophilin subfamily 3 member A2-like, Ig-C domain / SPRY-associated domain / SPRY-associated / PRY / Butyrophylin-like, SPRY domain / SPRY domain / B30.2/SPRY domain / B30.2/SPRY domain profile. / B30.2/SPRY domain superfamily / Domain in SPla and the RYanodine Receptor. / SPRY domain / Immunoglobulin V-Type / Immunoglobulin V-set domain / Immunoglobulin V-set domain / Immunoglobulin subtype / Immunoglobulin / Concanavalin A-like lectin/glucanase domain superfamily / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Butyrophilin subfamily 3 member A1 / Butyrophilin subfamily 3 member A2 / Butyrophilin subfamily 2 member A1
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.34 Å
AuthorsZhang M / Wang YQ / Xiao JY
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32325018 China
CitationJournal: Immunity / Year: 2025
Title: Structures of butyrophilin multimers reveal a plier-like mechanism for Vγ9Vδ2 T cell receptor activation.
Authors: Mai Zhang / Yiqing Wang / Ningning Cai / Yingying Qu / Xianqiang Ma / Jing Xue / Xiaorui Chen / Xueguang Zhang / Junyu Xiao / Yonghui Zhang /
Abstract: Vγ9Vδ2 T cells, the major circulating human γδ T cell subset, respond to infections and tumors by recognizing phosphoantigens (pAgs) via transmembrane butyrophilins (BTN3A1, BTN3A2, and BTN2A1). ...Vγ9Vδ2 T cells, the major circulating human γδ T cell subset, respond to infections and tumors by recognizing phosphoantigens (pAgs) via transmembrane butyrophilins (BTN3A1, BTN3A2, and BTN2A1). Here, using cryoelectron microscopy, we resolved the structures of BTN multimers bound to the microbial pAg HMBPP alone and in complex with the T cell receptor (TCR). These structures reveal that BTN3A1 and BTN2A1 cooperate to sense pAgs through their intracellular B30.2 domains, whereas BTN3A2 and BTN2A1 interact extracellularly. TCR engagement triggers its conformational changes, allowing BTN2A1 to bind the Vγ9 chain laterally and BTN3A2 to interact apically with the Vδ2 chain's germline-encoded regions and CDR3 motif, as well as the Vγ9 CDR3. Our study uncovers a "plier-like gripping" mechanism, where BTN multimers bridge the TCR surface to drive activation. These findings establish a structural foundation for γδ T cell-targeted immunotherapies distinct from αβ T cell strategies reliant on major-histocompatibility-complex-mediated antigen presentation.
History
DepositionSep 28, 2024-
Header (metadata) releaseJun 18, 2025-
Map releaseJun 18, 2025-
UpdateJul 23, 2025-
Current statusJul 23, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_61732.png

Downloads & links

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Map

FileDownload / File: emd_61732.map.gz / Format: CCP4 / Size: 282.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationEMReady
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.95 Å/pix.
x 420 pix.
= 399. Å		0.95 Å/pix.
x 420 pix.
= 399. Å		0.95 Å/pix.
x 420 pix.
= 399. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.95 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 2.0
Minimum - Maximum-0.14773823 - 17.397814
Average (Standard dev.)-0.03581972 (±0.24416946)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions420420420
Spacing420420420
CellA=B=C: 399.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: B-factor sharpen

Fileemd_61732_additional_1.map
AnnotationB-factor sharpen
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_61732_half_map_1.map
Projections & Slices
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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_61732_half_map_2.map
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : HMBPP-primed BTN3A1-BTN3A2-BTN2A1 in complex with agonist antibod...

EntireName: HMBPP-primed BTN3A1-BTN3A2-BTN2A1 in complex with agonist antibody TH001
Components
  • Complex: HMBPP-primed BTN3A1-BTN3A2-BTN2A1 in complex with agonist antibody TH001
    • Protein or peptide: Butyrophilin subfamily 3 member A1
    • Protein or peptide: Butyrophilin subfamily 3 member A2
    • Protein or peptide: Butyrophilin subfamily 2 member A1
    • Protein or peptide: BTN3A agonist antibody TH001, variable domain of light chain
    • Protein or peptide: BTN3A agonist antibody TH001, variable domain of heavy chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: HMBPP-primed BTN3A1-BTN3A2-BTN2A1 in complex with agonist antibod...

SupramoleculeName: HMBPP-primed BTN3A1-BTN3A2-BTN2A1 in complex with agonist antibody TH001
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3, #5, #4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Butyrophilin subfamily 3 member A1

MacromoleculeName: Butyrophilin subfamily 3 member A1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 58.247715 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QFSVLGPSGP ILAMVGEDAD LPCHLFPTMS AETMELKWVS SSLRQVVNVY ADGKEVEDRQ SAPYRGRTSI LRDGITAGKA ALRIHNVTA SDSGKYLCYF QDGDFYEKAL VELKVAALGS DLHVDVKGYK DGGIHLECRS TGWYPQPQIQ WSNNKGENIP T VEAPVVAD ...String:
QFSVLGPSGP ILAMVGEDAD LPCHLFPTMS AETMELKWVS SSLRQVVNVY ADGKEVEDRQ SAPYRGRTSI LRDGITAGKA ALRIHNVTA SDSGKYLCYF QDGDFYEKAL VELKVAALGS DLHVDVKGYK DGGIHLECRS TGWYPQPQIQ WSNNKGENIP T VEAPVVAD GVGLYAVAAS VIMRGSSGEG VSCTIRSSLL GLEKTASISI ADPFFRSAQR WIAALAGTLP VLLLLLGGAG YF LWQQQEE KKTQFRKKKR EQELREMAWS TMKQEQSTRV KLLEELRWRS IQYASRGERH SAYNEWKKAL FKPADVILDP KTA NPILLV SEDQRSVQRA KEPQDLPDNP ERFNWHYCVL GCESFISGRH YWEVEVGDRK EWHIGVCSKN VQRKGWVKMT PENG FWTMG LTDGNKYRTL TEPRTNLKLP KPPKKVGVFL DYETGDISFY NAVDGSHIHT FLDVSFSEAL YPVFRILTLE PTALT ICPA GGGGSGGGGS GGGGSWSHPQ FEKGGGSGGG SGGSAWSHPQ FEK

UniProtKB: Butyrophilin subfamily 3 member A1

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Macromolecule #2: Butyrophilin subfamily 3 member A2

MacromoleculeName: Butyrophilin subfamily 3 member A2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 34.629918 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QFSVLGPSGP ILAMVGEDAD LPCHLFPTMS AETMELKWVS SSLRQVVNVY ADGKEVEDRQ SAPYRGRTSI LRDGITAGKA ALRIHNVTA SDSGKYLCYF QDGDFYEKAL VELKVAALGS NLHVEVKGYE DGGIHLECRS TGWYPQPQIQ WSNAKGENIP A VEAPVVAD ...String:
QFSVLGPSGP ILAMVGEDAD LPCHLFPTMS AETMELKWVS SSLRQVVNVY ADGKEVEDRQ SAPYRGRTSI LRDGITAGKA ALRIHNVTA SDSGKYLCYF QDGDFYEKAL VELKVAALGS NLHVEVKGYE DGGIHLECRS TGWYPQPQIQ WSNAKGENIP A VEAPVVAD GVGLYEVAAS VIMRGGSGEG VSCIIRNSLL GLEKTASISI ADPFFRSAQP WIAALAGTLP ILLLLLAGAS YF LWRQQKE ITALSSEIES EQEMKEMGYA ATEREISLRE SLQEELKRKK IQYLTRGEES SSDTNKSAGG GGSDYKDDDD K

UniProtKB: Butyrophilin subfamily 3 member A2

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Macromolecule #3: Butyrophilin subfamily 2 member A1

MacromoleculeName: Butyrophilin subfamily 2 member A1 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 60.015312 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QFIVVGPTDP ILATVGENTT LRCHLSPEKN AEDMEVRWFR SQFSPAVFVY KGGRERTEEQ MEEYRGRTTF VSKDISRGSV ALVIHNITA QENGTYRCYF QEGRSYDEAI LHLVVAGLGS KPLISMRGHE DGGIRLECIS RGWYPKPLTV WRDPYGGVAP A LKEVSMPD ...String:
QFIVVGPTDP ILATVGENTT LRCHLSPEKN AEDMEVRWFR SQFSPAVFVY KGGRERTEEQ MEEYRGRTTF VSKDISRGSV ALVIHNITA QENGTYRCYF QEGRSYDEAI LHLVVAGLGS KPLISMRGHE DGGIRLECIS RGWYPKPLTV WRDPYGGVAP A LKEVSMPD ADGLFMVTTA VIIRDKSVRN MSCSINNTLL GQKKESVIFI PESFMPSVSP CAVALPIIVV ILMIPIAVCI YW INKLQKE KKILSGEKEF ERETREIALK ELEKERVQKE EELQVKEKLQ EELRWRRTFL HAVDVVLDPD TAHPDLFLSE DRR SVRRCP FRHLGESVPD NPERFDSQPC VLGRESFASG KHYWEVEVEN VIEWTVGVCR DSVERKGEVL LIPQNGFWTL EMHK GQYRA VSSPDRILPL KESLCRVGVF LDYEAGDVSF YNMRDRSHIY TCPRSAFSVP VRPFFRLGCE DSPIFICPAL TGANG VTVP EEGLTLHRVG THQSLGGGGS WSHPQFEKGG GSGGGSGGSA WSHPQFEK

UniProtKB: Butyrophilin subfamily 2 member A1

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Macromolecule #4: BTN3A agonist antibody TH001, variable domain of heavy chain

MacromoleculeName: BTN3A agonist antibody TH001, variable domain of heavy chain
type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 12.819174 KDa
SequenceString:
EVHVKQSGAE LARPGTSVKL SCKASGYTFT DYYLNWVKQR TGQGLEWIGE IYPGGGNTYY NEKFKGKATL TADKSSSTAY MQLSSLTSE DSAVYFCARR TTVVGDYWGQ GTTLTVSS

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Macromolecule #5: BTN3A agonist antibody TH001, variable domain of light chain

MacromoleculeName: BTN3A agonist antibody TH001, variable domain of light chain
type: protein_or_peptide / ID: 5 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 12.253794 KDa
SequenceString:
DVLMTQTPLS LPVSLGDQAS ISCRSSQSIV NSKGNTYLEW YVQKPGQSPK LLIYKVSNRF SGVPDRFSGS GSGTDFTLKI SRVEAEDLG VYYCFQGSHV PWTFGGGTKL EIK

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Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 6 / 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: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.7 µm / Nominal defocus min: 1.3 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.34 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 479276
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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