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- PDB-9p1m: Cryo-EM structure of CD73 in complex with antibody Sym024 -

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Basic information

Entry
Database: PDB / ID: 9p1m
TitleCryo-EM structure of CD73 in complex with antibody Sym024
Components
  • 5'-nucleotidase
  • Antibody Heavy Chain
  • Antibody Light Chain
KeywordsHYDROLASE / Antigen-Antibody Complex / Drug Target
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 / IMP-specific 5'-nucleotidase / 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 / IMP-specific 5'-nucleotidase / AMP catabolic process / Purine catabolism / 5'-nucleotidase / 5'-nucleotidase activity / Nicotinate metabolism / 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 / membrane / identical protein binding / 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: 2.9 Å
AuthorsBansia, H. / Armbruster, E. / Des Georges, A.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Clin Cancer Res / Year: 2026
Title: Sym024 Interacts with a Unique Epitope on the CD73 Homodimer, Favoring Effective Bivalent Binding to Improve Anti-PD-1 Therapy.
Authors: Janus S Jakobsen / Michael M Grandal / Randi W Hansen / Harsh Bansia / Emily Armbruster / Isabelle Theret / Niels Jørgen Ø Skartved / Rikke Hald / Maria C Melander / Anne Worsaae / Matteo ...Authors: Janus S Jakobsen / Michael M Grandal / Randi W Hansen / Harsh Bansia / Emily Armbruster / Isabelle Theret / Niels Jørgen Ø Skartved / Rikke Hald / Maria C Melander / Anne Worsaae / Matteo Riva / Kristian Reckzeh / Laurent Vuillard / Johan Lantto / Amedee des Georges / Camilla Fröhlich /
Abstract: PURPOSE: Adenosine signaling may be a central immunosuppressive mechanism in several cancers, and blockade of the rate-limiting CD73 adenosine monophosphate (AMP)-to-adenosine enzyme has been ...PURPOSE: Adenosine signaling may be a central immunosuppressive mechanism in several cancers, and blockade of the rate-limiting CD73 adenosine monophosphate (AMP)-to-adenosine enzyme has been demonstrated to improve the clinical efficacy of programmed cell death protein (ligand) 1 [PD-(L)1] immune therapy. However, deep inhibition of CD73 activity could prove difficult in tumor environments with a constant AMP supply and high CD73 levels. In this study, we sought to identify, characterize, and benchmark a novel antagonistic anti-CD73 antibody, Sym024 (S95024), and to structurally decode its mode of action.
EXPERIMENTAL DESIGN: Sym024, selected via functional antibody repertoire screening, was tested against benchmark anti-CD73 antibodies in primary cell, cell line in vitro binding, CD73 enzymatic ...EXPERIMENTAL DESIGN: Sym024, selected via functional antibody repertoire screening, was tested against benchmark anti-CD73 antibodies in primary cell, cell line in vitro binding, CD73 enzymatic activity, and T-cell activation assays. Its in vivo tumor growth inhibition was examined in transplanted human or mouse tumors in immunocompetent or immunodeficient mice, and intratumoral enzymatic inhibition and immune cell recruitment were assessed. We investigated the Sym024-CD73 interaction using surface plasmon resonance, cryogenic electron microscopy, site-directed mutagenesis, and population-level complex formation through size-exclusion chromatography with light scatter mass detection. Preclinical safety and pharmacokinetics (PK) were assessed in monkeys.
RESULTS: Sym024 effectively blocked CD73 across a large range of enzyme expression levels, comparing favorably with benchmark anti-CD73 antibodies; it improved the efficacy of PD-1 blockade in vitro ...RESULTS: Sym024 effectively blocked CD73 across a large range of enzyme expression levels, comparing favorably with benchmark anti-CD73 antibodies; it improved the efficacy of PD-1 blockade in vitro as well as in vivo. Our structural data indicate that a unique one-to-one Sym024-CD73 interaction engenders this comprehensive inhibition. No preclinical safety flags were observed, and the PK profile of Sym024 supported a standard clinical dosing regimen.
CONCLUSIONS: The comprehensive CD73 inhibition exhibited by Sym024 may improve the efficacy of anti-PD-(L)1/anti-CD73 combination treatment.
History
DepositionJun 10, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 24, 2025Provider: repository / Type: Initial release
Revision 1.0Dec 24, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Dec 24, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Dec 24, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Jan 21, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.1Jan 21, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
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Revision 1.2Mar 25, 2026Group: Data collection / Database references / Category: citation / em_admin
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Revision 1.2Mar 25, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / Category: citation / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 5'-nucleotidase
B: 5'-nucleotidase
C: Antibody Light Chain
D: Antibody Heavy Chain
E: Antibody Light Chain
F: Antibody Heavy Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)265,34212
Polymers264,6386
Non-polymers7046
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#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: 59514.633 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: Cricetulus griseus (Chinese hamster)
References: UniProt: P21589, thymidylate 5'-phosphatase, 5'-nucleotidase, 5'-deoxynucleotidase, 7-methylguanosine nucleotidase, IMP-specific 5'-nucleotidase
#2: Antibody Antibody Light Chain


Mass: 23200.814 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293 / Production host: Homo sapiens (human)
#3: Antibody Antibody Heavy Chain


Mass: 49603.695 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293 / Production host: Homo sapiens (human)
#4: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#5: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
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 dimer bound to antibody Sym024 / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Cricetulus griseus (Chinese hamster)
Buffer solutionpH: 5.5
SpecimenConc.: 0.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: TFS TITAN THEMIS
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: 800 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.21.2_5419: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 286779 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00314180
ELECTRON MICROSCOPYf_angle_d0.55819295
ELECTRON MICROSCOPYf_dihedral_angle_d4.9112003
ELECTRON MICROSCOPYf_chiral_restr0.0452208
ELECTRON MICROSCOPYf_plane_restr0.0042485

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