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- EMDB-31499: CD25 in complex with Fab -

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Basic information

Entry
Database: EMDB / ID: EMD-31499
TitleCD25 in complex with Fab
Map dataCD25 Fab
Sample
  • Complex: CD25 in complex with Fab
    • Complex: CD25
      • Protein or peptide: Interleukin-2 receptor subunit alpha
    • Complex: FAB
      • Protein or peptide: Light chain of Fab
      • Protein or peptide: Heavy chain of Fab
Function / homology
Function and homology information


regulation of T cell tolerance induction / interleukin-2 receptor complex / interleukin-2 receptor activity / interleukin-2 binding / regulation of CD4-positive, alpha-beta T cell proliferation / regulation of T cell homeostatic proliferation / RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs) / interleukin-2-mediated signaling pathway / activated T cell proliferation / inflammatory response to antigenic stimulus ...regulation of T cell tolerance induction / interleukin-2 receptor complex / interleukin-2 receptor activity / interleukin-2 binding / regulation of CD4-positive, alpha-beta T cell proliferation / regulation of T cell homeostatic proliferation / RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs) / interleukin-2-mediated signaling pathway / activated T cell proliferation / inflammatory response to antigenic stimulus / Interleukin-2 signaling / positive regulation of T cell differentiation / activation-induced cell death of T cells / positive regulation of activated T cell proliferation / Interleukin receptor SHC signaling / negative regulation of T cell proliferation / Notch signaling pathway / negative regulation of inflammatory response / RAF/MAP kinase cascade / cell surface receptor signaling pathway / inflammatory response / immune response / external side of plasma membrane / apoptotic process / plasma membrane
Similarity search - Function
Interleukin-2 receptor alpha / Sushi repeat (SCR repeat) / Domain abundant in complement control proteins; SUSHI repeat; short complement-like repeat (SCR) / Sushi/SCR/CCP domain / Sushi/CCP/SCR domain profile. / Sushi/SCR/CCP superfamily
Similarity search - Domain/homology
Interleukin-2 receptor subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsLiu C
CitationJournal: Sci Rep / Year: 2021
Title: Two novel human anti-CD25 antibodies with antitumor activity inversely related to their affinity and in vitro activity.
Authors: Deyong Song / Xiu Liu / Chuangchuang Dong / Qiaoping Wang / Chunjie Sha / Chuan Liu / Zhenfei Ning / Jing Han / Hong Liu / Mengqi Zong / Yanyan Zhao / Ying Li / Guangsheng Liu / Xin Shao / Changlin Dou /
Abstract: High tumor regulatory T (Treg) cell infiltration is associated with poor prognosis of many cancers. CD25 is highly expressed on tumor Treg cells and is a potential target for Treg deletion. ...High tumor regulatory T (Treg) cell infiltration is associated with poor prognosis of many cancers. CD25 is highly expressed on tumor Treg cells and is a potential target for Treg deletion. Previously characterized anti-CD25 antibodies appear to have limited efficacy in tumor inhibition. Here we identified two human anti-CD25 antibodies, BA9 and BT942, which did not prevent the activation of IL-2R signaling pathway by IL-2. BT942 had weaker binding and cytotoxic activity to human CD25-expressing cell lines than BA9. But both demonstrated significant tumor growth inhibition in early and late-stage animal cancer models. BT942 resulted in a higher expansion of CD8 T cells and CD4 T cells in tumor microenvironment in mouse MC38 model compared to BA9. BT942 also demonstrated significant higher tumor growth inhibition and higher expansion of CD8 T cells and CD4 T cells in combination with an anti-PD1 antibody. Pharmacokinetic study of BT942 in cynomolgus monkeys demonstrated a half-life of 206.97 ± 19.03 h. Structural analysis by cryo-EM revealed that BT942 recognizes an epitope on opposite side of the CD25-IL-2 binding site, consistent with no IL-2 signaling blockade in vitro. BT942 appears to be an excellent candidate for cancer immunotherapy.
History
DepositionJul 5, 2021-
Header (metadata) releaseJan 12, 2022-
Map releaseJan 12, 2022-
UpdateJan 12, 2022-
Current statusJan 12, 2022Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.189
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.189
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7f9w
  • Surface level: 0.189
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_31499.png

Downloads & links

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Map

FileDownload / File: emd_31499.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCD25 Fab
Voxel sizeX=Y=Z: 0.54 Å
Density
Contour LevelBy AUTHOR: 0.189 / Movie #1: 0.189
Minimum - Maximum-0.6488711 - 1.1958737
Average (Standard dev.)5.1606952e-05 (±0.023495127)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 194.40001 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.540.540.54
M x/y/z360360360
origin x/y/z0.0000.0000.000
length x/y/z194.400194.400194.400
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS360360360
D min/max/mean-0.6491.1960.000

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Supplemental data

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Sample components

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Entire : CD25 in complex with Fab

EntireName: CD25 in complex with Fab
Components
  • Complex: CD25 in complex with Fab
    • Complex: CD25
      • Protein or peptide: Interleukin-2 receptor subunit alpha
    • Complex: FAB
      • Protein or peptide: Light chain of Fab
      • Protein or peptide: Heavy chain of Fab

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Supramolecule #1: CD25 in complex with Fab

SupramoleculeName: CD25 in complex with Fab / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Details: Fab fragment generated by proteolytic cleavage of IgG antibody

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Supramolecule #2: CD25

SupramoleculeName: CD25 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)

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Supramolecule #3: FAB

SupramoleculeName: FAB / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2-#3
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)

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Macromolecule #1: Interleukin-2 receptor subunit alpha

MacromoleculeName: Interleukin-2 receptor subunit alpha / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 18.354754 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
DDPPEIPHAT FKAMAYKEGT MLNCECKRGF RRIKSGSLYM LCTGNSSHSS WDNQCQCTSS ATRNTTKQVT PQPEEQKERK TTEMQSPMQ PVDQASLPGH CREPPPWENE ATERIYHFVV GQMVYYQCVQ GYRALHRGPA ESVCKMTHGK TRWTQPQLIC T G

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Macromolecule #2: Light chain of Fab

MacromoleculeName: Light chain of Fab / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.308867 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: DIQMTQSPDS LAVSLGERAT INCKSSQSVL YSSNNKNYLA WYQQKPGQPP KLLIYWASTR ESGVPDRFSG SGSGTDFTLT ISSLQAEDV AVYYCQQYYS TPYTFGQGTK VEIKRTVAAP SVFIFPPSDE QLKSGTASVV CLLNNFYPRE AKVQWKVDNA L QSGNSQES ...String:
DIQMTQSPDS LAVSLGERAT INCKSSQSVL YSSNNKNYLA WYQQKPGQPP KLLIYWASTR ESGVPDRFSG SGSGTDFTLT ISSLQAEDV AVYYCQQYYS TPYTFGQGTK VEIKRTVAAP SVFIFPPSDE QLKSGTASVV CLLNNFYPRE AKVQWKVDNA L QSGNSQES VTEQDSKDST YSLSSTLTLS KADYEKHKVY ACEVTHQGLS SPVTKSFNRG EC

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Macromolecule #3: Heavy chain of Fab

MacromoleculeName: Heavy chain of Fab / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 49.520723 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: QVQLVQSGAE VKKPGSSVKV SCKASGGTFS SDAINWVRQA PGQGLEWMGR IIPIFGVADY AQKFQGRVTL TADKSTSTAY MDLSSLRSE DTAVFYCARE RGDYSNFWYF DLWGRGTLVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV T VSWNSGAL ...String:
QVQLVQSGAE VKKPGSSVKV SCKASGGTFS SDAINWVRQA PGQGLEWMGR IIPIFGVADY AQKFQGRVTL TADKSTSTAY MDLSSLRSE DTAVFYCARE RGDYSNFWYF DLWGRGTLVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV T VSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL GTQTYICNVN HKPSNTKVDK KVEPKSCDKT HTCPPCPAPE LL GGPSVFL FPPKPKDTLM ISRTPEVTCV VVDVSHEDPE VKFNWYVDGV EVHNAKTKPR EEQYNSTYRV VSVLTVLHQD WLN GKEYKC KVSNKALPAP IEKTISKAKG QPREPQVYTL PPSRDELTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTP PVLDS DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPGK

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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

Concentration0.2 mg/mL
BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 149373
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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