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- EMDB-60281: CD73 bound with HB0045 -

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Basic information

Entry
Database: EMDB / ID: EMD-60281
TitleCD73 bound with HB0045
Map data
Sample
  • Complex: CD73 complexed with HB0017 antibody coaktail
    • Protein or peptide: 5'-nucleotidase
    • Protein or peptide: HB0038 Fab light chain
    • Protein or peptide: HB0038 Fab heavy chain
    • Protein or peptide: HB0039 Fab heavy chain
    • Protein or peptide: HB0039 Fab light chain
  • Ligand: ZINC ION
  • Ligand: SODIUM ION
  • Ligand: CALCIUM ION
KeywordsCD73 / complex / antibody coaktail / IMMUNE SYSTEM
Function / homology
Function and homology information


thymidylate 5'-phosphatase / : / ADP catabolic process / 5'-deoxynucleotidase / 5'-deoxynucleotidase activity / 7-methylguanosine nucleotidase / adenosine biosynthetic process / inhibition of non-skeletal tissue mineralization / Pyrimidine catabolism / AMP catabolic process ...thymidylate 5'-phosphatase / : / ADP catabolic process / 5'-deoxynucleotidase / 5'-deoxynucleotidase activity / 7-methylguanosine nucleotidase / adenosine biosynthetic process / inhibition of non-skeletal tissue mineralization / Pyrimidine catabolism / AMP catabolic process / : / IMP-specific 5'-nucleotidase / : / Nicotinate metabolism / Purine catabolism / : / 5'-nucleotidase / 5'-nucleotidase activity / leukocyte cell-cell adhesion / DNA metabolic process / response to ATP / ATP metabolic process / Purinergic signaling in leishmaniasis infection / calcium ion homeostasis / negative regulation of inflammatory response / external side of plasma membrane / nucleotide binding / cell surface / extracellular exosome / zinc ion binding / nucleoplasm / identical protein binding / membrane / plasma membrane / cytosol
Similarity search - Function
5'-nucleotidase signature 1. / 5'-Nucleotidase, conserved site / 5'-nucleotidase signature 2. / 5'-Nucleotidase, C-terminal / 5'-nucleotidase, C-terminal domain / 5'-Nucleotidase/apyrase / 5'-Nucleotidase, C-terminal domain superfamily / Calcineurin-like phosphoesterase domain, ApaH type / Calcineurin-like phosphoesterase / Metallo-dependent phosphatase-like
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.06 Å
AuthorsXu J / Wan L / He Y
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Commun / Year: 2024
Title: An antibody cocktail targeting two different CD73 epitopes enhances enzyme inhibition and tumor control.
Authors: Jin-Gen Xu / Shi Chen / Yang He / Xi Zhu / Yanting Wang / Zhifeng Ye / Jin Chuan Zhou / Xuanhui Wu / Lei Zhang / Xiaochen Ren / Huifeng Jia / Haijia Yu / Xiaoyue Wei / Yujie Feng / Xiaofang ...Authors: Jin-Gen Xu / Shi Chen / Yang He / Xi Zhu / Yanting Wang / Zhifeng Ye / Jin Chuan Zhou / Xuanhui Wu / Lei Zhang / Xiaochen Ren / Huifeng Jia / Haijia Yu / Xiaoyue Wei / Yujie Feng / Xiaofang Chen / Xiaopei Cui / Xianfei Pan / Shaojie Wang / Simin Xia / Hongjie Shang / Yueqing Pu / Wei Xu / Haidong Li / Qian Chen / Zeyu Chen / Manfu Wang / Xiaodong Yan / Hui Shi / Mingwei Li / Yisui Xia / Roberto Bellelli / Shunli Dong / Jun He / Jun Huang / Chen-Leng Cai / Xiangyang Zhu / Yifan Zhan / Li Wan /
Abstract: CD73, an ectoenzyme responsible for adenosine production, is often elevated in immuno-suppressive tumor environments. Inhibition of CD73 activity holds great promise as a therapeutic strategy for ...CD73, an ectoenzyme responsible for adenosine production, is often elevated in immuno-suppressive tumor environments. Inhibition of CD73 activity holds great promise as a therapeutic strategy for CD73-expressing cancers. In this study, we have developed a therapeutic anti-human CD73 antibody cocktail, HB0045. HB0045 is a 1:1 mixture of two humanized monoclonal IgG1 antibodies (mAbs), HB0038 and HB0039. The cocktail not only harnesses the advantages of its parental mAbs in enzyme inhibition but also shows a significantly greater capability of promoting T cell proliferation in vitro. Structural analyses show that HB0045 effectively locks the CD73 dimer in a "partially open" non-active conformation through a double lock mechanism. In various animal models of syngeneic and xenograft tumors, HB0045 inhibits tumor growth more potently than the single mAbs. Collectively, our findings provide functional and structural insights into the mechanism of a CD73-targeting antibody cocktail.
History
DepositionMay 28, 2024-
Header (metadata) releaseFeb 5, 2025-
Map releaseFeb 5, 2025-
UpdateFeb 19, 2025-
Current statusFeb 19, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_60281.png

Downloads & links

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Map

FileDownload / File: emd_60281.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 512 pix.
= 433.152 Å		0.85 Å/pix.
x 512 pix.
= 433.152 Å		0.85 Å/pix.
x 512 pix.
= 433.152 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.846 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.134
Minimum - Maximum-0.7935505 - 1.2509128
Average (Standard dev.)-0.00054605585 (±0.022542188)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 433.152 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_60281_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_60281_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_60281_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : CD73 complexed with HB0017 antibody coaktail

EntireName: CD73 complexed with HB0017 antibody coaktail
Components
  • Complex: CD73 complexed with HB0017 antibody coaktail
    • Protein or peptide: 5'-nucleotidase
    • Protein or peptide: HB0038 Fab light chain
    • Protein or peptide: HB0038 Fab heavy chain
    • Protein or peptide: HB0039 Fab heavy chain
    • Protein or peptide: HB0039 Fab light chain
  • Ligand: ZINC ION
  • Ligand: SODIUM ION
  • Ligand: CALCIUM ION

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Supramolecule #1: CD73 complexed with HB0017 antibody coaktail

SupramoleculeName: CD73 complexed with HB0017 antibody coaktail / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 0.63 kDa/nm

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Macromolecule #1: 5'-nucleotidase

MacromoleculeName: 5'-nucleotidase / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: thymidylate 5'-phosphatase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 58.155199 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: AWELTILHTN DVHSRLEQTS EDSSKCVNAS RCMGGVARLF TKVQQIRRAE PNVLLLDAGD QYQGTIWFTV YKGAEVAHFM NALRYDAMA LGNHEFDNGV EGLIEPLLKE AKFPILSANI KAKGPLASQI SGLYLPYKVL PVGDEVVGIV GYTSKETPFL S NPGTNLVF ...String:
AWELTILHTN DVHSRLEQTS EDSSKCVNAS RCMGGVARLF TKVQQIRRAE PNVLLLDAGD QYQGTIWFTV YKGAEVAHFM NALRYDAMA LGNHEFDNGV EGLIEPLLKE AKFPILSANI KAKGPLASQI SGLYLPYKVL PVGDEVVGIV GYTSKETPFL S NPGTNLVF EDEITALQPE VDKLKTLNVN KIIALGHSGF EMDKLIAQKV RGVDVVVGGH SNTFLYTGNP PSKEVPAGKY PF IVTSDDG RKVPVVQAYA FGKYLGYLKI EFDERGNVIS SHGNPILLNS SIPEDPSIKA DINKWRIKLD NYSTQELGKT IVY LDGSSQ SCRFRECNMG NLICDAMINN NLRHTDEMFW NHVSMCILNG GGIRSPIDER NNGTITWENL AAVLPFGGTF DLVQ LKGST LKKAFEHSVH RYGQSTGEFL QVGGIHVVYD LSRKPGDRVV KLDVLCTKCR VPSYDPLKMD EVYKVILPNF LANGG DGFQ MIKDELLRHD SGDQDINVVS TYISKMKVIY PAVEGRIKFS

UniProtKB: 5'-nucleotidase

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Macromolecule #2: HB0038 Fab light chain

MacromoleculeName: HB0038 Fab light chain / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.32049 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
DIQMTQSPSS LSASVGDRVT ITCRASQDVG TAEAWYQQKP GKAPKLLIYW ASTRHTGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQ QYSSYPLTFG QGTKL

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Macromolecule #3: HB0038 Fab heavy chain

MacromoleculeName: HB0038 Fab heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.596152 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
QVQLVESGGG LVKPGGSLRL SCAASGFTFS KYAMSWIRQA PGKGLEWVAE ISSGGGYINY ADSVKGRFTI SRDNAKNSLY LQMNSLRAE DTAVYYCARA IYYYGSSYNY YAMDYWGQGT TVTVS

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Macromolecule #4: HB0039 Fab heavy chain

MacromoleculeName: HB0039 Fab heavy chain / type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.236699 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
QVQLVQSGAE VKKPGASVKL SCKASGYTFT SYWIHWVRQA PGQGLEWIGM IHPNSGSTYY NEKFKGRATL TVDKSTSTAY MELSSLRSE DTAVYYCARY YGSDYEWYFD VWGQGTTV

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Macromolecule #5: HB0039 Fab light chain

MacromoleculeName: HB0039 Fab light chain / type: protein_or_peptide / ID: 5 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.338706 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
IQMTQSPSSM SASVGDRVTI TCKASQNVRT AVVWYQQKPG KAPKALIYLA SNRHTGVPDR FSGSGSGTDF TLTISSLQPE DFATYFCLQ HWNYPYTFGQ GTKL

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Macromolecule #6: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 6 / Number of copies: 4 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #7: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 7 / Number of copies: 2
Molecular weightTheoretical: 22.99 Da

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Macromolecule #8: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 8 / Number of copies: 2 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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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
GridModel: Quantifoil / Material: COPPER / Support film - Material: CARBON / Support film - topology: CONTINUOUS
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 55.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6tvg


Details: CD73 model
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.06 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 62605
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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