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- PDB-9mqr: A8 Fab in complex with CD97 -

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Basic information

Entry
Database: PDB / ID: 9mqr
TitleA8 Fab in complex with CD97
Components
  • Adhesion G protein-coupled receptor E5
  • Heavy chain of A8 Fab
  • Light chain of A8 Fab
KeywordsIMMUNE SYSTEM / Protein complex / Antibody / Adhesion G protein-coupled receptor
Function / homology
Function and homology information


Class B/2 (Secretin family receptors) / secretory granule membrane / G protein-coupled receptor activity / adenylate cyclase-activating G protein-coupled receptor signaling pathway / transmembrane signaling receptor activity / cell-cell signaling / cell surface receptor signaling pathway / cell adhesion / immune response / G protein-coupled receptor signaling pathway ...Class B/2 (Secretin family receptors) / secretory granule membrane / G protein-coupled receptor activity / adenylate cyclase-activating G protein-coupled receptor signaling pathway / transmembrane signaling receptor activity / cell-cell signaling / cell surface receptor signaling pathway / cell adhesion / immune response / G protein-coupled receptor signaling pathway / inflammatory response / focal adhesion / calcium ion binding / Neutrophil degranulation / extracellular exosome / membrane / plasma membrane
Similarity search - Function
GPCR, family 2, ADGRE2/ADGRE5 / GAIN domain superfamily / GPCR proteolysis site, GPS, motif / : / GPS motif / GAIN-B domain profile. / G-protein-coupled receptor proteolytic site domain / : / Calcium-binding EGF domain / G-protein coupled receptors family 2 signature 2. ...GPCR, family 2, ADGRE2/ADGRE5 / GAIN domain superfamily / GPCR proteolysis site, GPS, motif / : / GPS motif / GAIN-B domain profile. / G-protein-coupled receptor proteolytic site domain / : / Calcium-binding EGF domain / G-protein coupled receptors family 2 signature 2. / GPCR, family 2, secretin-like, conserved site / GPCR, family 2, secretin-like / 7 transmembrane receptor (Secretin family) / GPCR, family 2-like / G-protein coupled receptors family 2 profile 2. / EGF-type aspartate/asparagine hydroxylation site / EGF-like calcium-binding, conserved site / Calcium-binding EGF-like domain signature. / Aspartic acid and asparagine hydroxylation site. / EGF-like calcium-binding domain / Calcium-binding EGF-like domain / Epidermal growth factor-like domain. / EGF-like domain profile. / Growth factor receptor cysteine-rich domain superfamily / EGF-like domain
Similarity search - Domain/homology
Adhesion G protein-coupled receptor E5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.16 Å
AuthorsHattori, T. / Bang, I. / Fang, M. / Koide, S.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01 CA251669 United States
Citation
Journal: Proc Natl Acad Sci U S A / Year: 2025
Title: Engineering antibody-drug conjugates targeting an adhesion GPCR, CD97.
Authors: Takamitsu Hattori / Michelle Wang / Alexis D Corrado / Suzanne Gross / Michelle Fang / Injin Bang / Nainita Roy / Iryna Berezniuk / Hayley Donaldson / Karenna Groff / Niklas Ravn-Boess / ...Authors: Takamitsu Hattori / Michelle Wang / Alexis D Corrado / Suzanne Gross / Michelle Fang / Injin Bang / Nainita Roy / Iryna Berezniuk / Hayley Donaldson / Karenna Groff / Niklas Ravn-Boess / Akiko Koide / Dimitris G Placantonakis / Christopher Y Park / Shohei Koide /
Abstract: Adhesion G protein-coupled receptors (aGPCRs) are key cell-adhesion molecules involved in many cellular functions and contribute to human diseases, including cancer. aGPCRs are characterized by large ...Adhesion G protein-coupled receptors (aGPCRs) are key cell-adhesion molecules involved in many cellular functions and contribute to human diseases, including cancer. aGPCRs are characterized by large extracellular regions that could serve as readily accessible antigens. However, the potential of aGPCRs as targets for biologic therapeutics has not been extensively explored. CD97, also known as ADGRE5, is an aGPCR that is upregulated in various cancer types, including acute myeloid leukemia (AML) and glioblastoma (GBM), and their respective cancer stem cells. Here, we developed antibody-drug conjugates (ADCs) targeting CD97 and assessed their efficacy against AML and GBM cells. We generated a panel of synthetic human antibodies targeting distinct epitopes of CD97, from which we identified an antibody that was efficiently internalized. This antibody binds to all isoforms of human CD97 but not to its close homolog, EMR2. Structure determination by single-particle cryo-electron microscopy revealed that this antibody targets the CD97 GPCR autoproteolysis-inducing (GAIN) domain, whose presence is conserved in aGPCRs, through an unconventional binding mode where it extensively utilizes the light chain framework for antigen recognition. Screening of conjugation methods and payloads resulted in a stable ADC that effectively killed AML and GBM cell lines, as well as patient-derived GBM stem cells, with minimal cytotoxicity against peripheral blood mononuclear cells from healthy donors. Our study demonstrates the therapeutic potential of targeting CD97, as well as the aGPCR GAIN domain in general, and uncovers a previously unrecognized surface that an antibody can utilize for antigen recognition.
#1: Journal: Biorxiv / Year: 2025
Title: Engineering Antibody-Drug Conjugates targeting an Adhesion GPCR, CD97
Authors: Hattori, T. / Wang, M. / Corrado, A.D. / Gross, S. / Fang, M. / Bang, I. / Roy, N. / Berezniuk, I. / Donaldson, H. / Groff, K. / Ravn-Boess, N. / Koide, A. / Placantonakis, D.G. / Park, C.Y. / Koide, S.
History
DepositionJan 6, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 24, 2025Provider: repository / Type: Initial release
Revision 1.1Oct 15, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Adhesion G protein-coupled receptor E5
D: Heavy chain of A8 Fab
E: Light chain of A8 Fab


Theoretical massNumber of molelcules
Total (without water)108,5273
Polymers108,5273
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, The binding of A8 Fab (chains D and E) to CD97 (chain A) was confirmed by gel filtration and the immunoprecipitation-based binding assay.
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Adhesion G protein-coupled receptor E5 / Leukocyte antigen CD97


Mass: 59277.082 Da / Num. of mol.: 1 / Mutation: S531A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ADGRE5, CD97 / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P48960
#2: Antibody Heavy chain of A8 Fab


Mass: 26019.936 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#3: Antibody Light chain of A8 Fab


Mass: 23229.785 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
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: A8 Fab in complex with CD97 / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.11 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Cricetulus griseus (Chinese hamster)
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
150 mMTris(hydroxymethyl)aminomethane hydrochlorideTris-HCl1
2150 mMsodium chlorideNaCl1
310 mMcalcium chlorideCaCl21
SpecimenConc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R0.6/1
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 277.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 48.53 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.16 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 89719 / Symmetry type: POINT
Atomic model building
IDPDB-ID 3D fitting-IDAccession codeInitial refinement model-IDSource nameType
16AZ2

6az2

16AZ21PDBexperimental model
21AF-P48960-F12AlphaFoldin silico model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0043809
ELECTRON MICROSCOPYf_angle_d0.5025167
ELECTRON MICROSCOPYf_dihedral_angle_d4.224517
ELECTRON MICROSCOPYf_chiral_restr0.043581
ELECTRON MICROSCOPYf_plane_restr0.004656

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