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- PDB-8znz: CD73 bound with HB0045 -

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Basic information

Entry
Database: PDB / ID: 8znz
TitleCD73 bound with HB0045
Components
  • 5'-nucleotidase
  • HB0038 Fab heavy chain
  • HB0038 Fab light chain
  • HB0039 Fab heavy chain
  • HB0039 Fab light chain
KeywordsIMMUNE SYSTEM / CD73 / complex / antibody coaktail
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 / Purinergic signaling in leishmaniasis infection / ATP metabolic process / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.06 Å
AuthorsXu, J. / Wan, L. / He, Y.
Funding support China, 1items
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, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Feb 5, 2025Provider: repository / Type: Initial release
Revision 1.1Feb 19, 2025Group: Data collection / Source and taxonomy / Category: em_admin / entity_src_gen
Item: _em_admin.last_update / _entity_src_gen.pdbx_gene_src_ncbi_taxonomy_id / _entity_src_gen.pdbx_gene_src_scientific_name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 5'-nucleotidase
E: HB0038 Fab light chain
F: HB0038 Fab heavy chain
I: HB0039 Fab heavy chain
J: HB0039 Fab light chain
B: 5'-nucleotidase
C: HB0038 Fab light chain
D: HB0038 Fab heavy chain
G: HB0039 Fab heavy chain
H: HB0039 Fab light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)215,68218
Polymers215,29410
Non-polymers3888
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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Protein , 1 types, 2 molecules AB

#1: Protein 5'-nucleotidase / 5'-NT / 5'-deoxynucleotidase / Ecto-5'-nucleotidase / IMP-specific 5'-nucleotidase / Thymidylate 5'- ...5'-NT / 5'-deoxynucleotidase / Ecto-5'-nucleotidase / IMP-specific 5'-nucleotidase / Thymidylate 5'-phosphatase


Mass: 58155.199 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NT5E, NT5, NTE / Production host: Escherichia coli (E. coli)
References: UniProt: P21589, thymidylate 5'-phosphatase, 5'-nucleotidase, 5'-deoxynucleotidase, 7-methylguanosine nucleotidase, IMP-specific 5'-nucleotidase

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Antibody , 4 types, 8 molecules ECFDIGJH

#2: Antibody HB0038 Fab light chain


Mass: 11320.490 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#3: Antibody HB0038 Fab heavy chain


Mass: 13596.152 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#4: Antibody HB0039 Fab heavy chain


Mass: 13236.699 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#5: Antibody HB0039 Fab light chain


Mass: 11338.706 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)

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Non-polymers , 3 types, 8 molecules

#6: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#7: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#8: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca

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Details

Has ligand of interestN
Has protein modificationY

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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: CD73 complexed with HB0017 antibody coaktail / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Molecular weightValue: 0.63 kDa/nm / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid type: Quantifoil
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 3000 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 55 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.06 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 62605 / Symmetry type: POINT

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