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- EMDB-60686: Cryo-EM structure for the GPRC5D complexed with Talquetamab Fab -

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Basic information

Entry
Database: EMDB / ID: EMD-60686
TitleCryo-EM structure for the GPRC5D complexed with Talquetamab Fab
Map data
Sample
  • Complex: GPCR antibody complex
    • Complex: antibody
      • Protein or peptide: Talquetamab Fab (anti-GPRC5D) Heavy chain
      • Protein or peptide: Talquetamab Fab (anti-GPRC5D) Light chain
    • Complex: GPCR
      • Protein or peptide: G-protein coupled receptor family C group 5 member D
  • Ligand: CHOLESTEROL
KeywordsTalquetamab / class C GPCR / multiple myeloma / bispecific antibody / MEMBRANE PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


protein kinase activator activity / G protein-coupled receptor activity / receptor complex / intracellular membrane-bounded organelle / extracellular exosome / plasma membrane
Similarity search - Function
: / GPCR family 3, C-terminal / 7 transmembrane sweet-taste receptor of 3 GCPR
Similarity search - Domain/homology
G-protein coupled receptor family C group 5 member D
Similarity search - Component
Biological speciesMus musculus (house mouse) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.65 Å
AuthorsJeong J / Shin J / Park J / Cho Y
Funding support Korea, Republic Of, 1 items
OrganizationGrant numberCountry
National Research Foundation (NRF, Korea)2021R1A2C301335711 Korea, Republic Of
CitationJournal: J Mol Biol / Year: 2024
Title: Structural Basis for the Recognition of GPRC5D by Talquetamab, a Bispecific Antibody for Multiple Myeloma.
Authors: Jihong Jeong / Junhyeon Park / Geun Young Mo / Jinwoo Shin / Yunje Cho /
Abstract: Multiple myeloma (MM) is a complex hematological malignancy characterized by abnormal antibody production from plasma cells. Despite advances in the treatment, many patients experience disease ...Multiple myeloma (MM) is a complex hematological malignancy characterized by abnormal antibody production from plasma cells. Despite advances in the treatment, many patients experience disease relapse or become refractory to treatment. G-protein-coupled receptor class C group 5 member D (GPRC5D), an orphan GPCR predominantly expressed in MM cells, is emerging as a promising target for MM immunotherapy. Talquetamab, a Food and Drug Administration-approved T-cell-directing bispecific antibody developed for treatment of MM, targets GPRC5D. Here, we elucidate the structure of GPRC5D complexed with the Fab fragment of talquetamab, using cryo-electron microscopy, providing the basis for recognition of GPRC5D by the bispecific antibody. GPRC5D forms a symmetric homodimer with the interface between transmembrane helix (TM) 4 of one protomer and TM4/5 of the other protomer. A single talquetamab Fab interacts with the GPRC5D dimer with its orientation toward the dimer interface. All six complementarity-determining regions of talquetamab engage with extracellular loops and TM3/5/7. In particular, the side-chain of an arginine residue from the antibody penetrates into a shallow pocket on the extracellular surface of GPRC5D. The structure offers insights for optimizing antibody design against GPRC5D for relapsed or refractory MM therapy.
History
DepositionJul 2, 2024-
Header (metadata) releaseSep 11, 2024-
Map releaseSep 11, 2024-
UpdateSep 11, 2024-
Current statusSep 11, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_60686.png

Downloads & links

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Map

FileDownload / File: emd_60686.map.gz / Format: CCP4 / Size: 193.2 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 370 pix.
= 305.805 Å		0.83 Å/pix.
x 370 pix.
= 305.805 Å		0.83 Å/pix.
x 370 pix.
= 305.805 Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8265 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.3
Minimum - Maximum-0.74638516 - 1.2379642
Average (Standard dev.)-0.00020127432 (±0.030147834)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions370370370
Spacing370370370
CellA=B=C: 305.805 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_60686_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_60686_half_map_2.map
Projections & Slices
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Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : GPCR antibody complex

EntireName: GPCR antibody complex
Components
  • Complex: GPCR antibody complex
    • Complex: antibody
      • Protein or peptide: Talquetamab Fab (anti-GPRC5D) Heavy chain
      • Protein or peptide: Talquetamab Fab (anti-GPRC5D) Light chain
    • Complex: GPCR
      • Protein or peptide: G-protein coupled receptor family C group 5 member D
  • Ligand: CHOLESTEROL

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Supramolecule #1: GPCR antibody complex

SupramoleculeName: GPCR antibody complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3

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Supramolecule #2: antibody

SupramoleculeName: antibody / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2
Source (natural)Organism: Mus musculus (house mouse)

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Supramolecule #3: GPCR

SupramoleculeName: GPCR / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Talquetamab Fab (anti-GPRC5D) Heavy chain

MacromoleculeName: Talquetamab Fab (anti-GPRC5D) Heavy chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 25.137211 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: QVQLVQSGAE VKKPGASVKV SCKASGYSFT GYTMNWVRQA PGQGLEWMGL INPYNSDTNY AQKLQGRVTM TTDTSTSTAY MELRSLRSD DTAVYYCARV ALRVALDYWG QGTLVTVSSA STKGPSVFPL APCSRSTSES TAALGCLVKD YFPEPVTVSW N SGALTSGV ...String:
QVQLVQSGAE VKKPGASVKV SCKASGYSFT GYTMNWVRQA PGQGLEWMGL INPYNSDTNY AQKLQGRVTM TTDTSTSTAY MELRSLRSD DTAVYYCARV ALRVALDYWG QGTLVTVSSA STKGPSVFPL APCSRSTSES TAALGCLVKD YFPEPVTVSW N SGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTKT YTCNVDHKPS NTKVDKRVES KYGLVPRGSH HHHHH

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Macromolecule #2: Talquetamab Fab (anti-GPRC5D) Light chain

MacromoleculeName: Talquetamab Fab (anti-GPRC5D) Light chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.666236 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: DIQMTQSPSS LSASVGDRVT ITCKASQNVA THVGWYQQKP GKAPKRLIYS ASYRYSGVPS RFSGSGSGTE FTLTISNLQP EDFATYYCQ QYNRYPYTFG QGTKLEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS ...String:
DIQMTQSPSS LSASVGDRVT ITCKASQNVA THVGWYQQKP GKAPKRLIYS ASYRYSGVPS RFSGSGSGTE FTLTISNLQP EDFATYYCQ QYNRYPYTFG QGTKLEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC

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Macromolecule #3: G-protein coupled receptor family C group 5 member D

MacromoleculeName: G-protein coupled receptor family C group 5 member D / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.540027 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MVDMYKDCIE STGDYFLLCD AEGPWGIILE SLAILGIVVT ILLLLAFLFL MRKIQDCSQW NVLPTQLLFL LSVLGLFGLA FAFIIELNQ QTAPVRYFLF GVLFALCFSC LLAHASNLVK LVRGCVSFSW TTILCIAIGC SLLQIIIATE YVTLIMTRGM M FVNMTPCQ ...String:
MVDMYKDCIE STGDYFLLCD AEGPWGIILE SLAILGIVVT ILLLLAFLFL MRKIQDCSQW NVLPTQLLFL LSVLGLFGLA FAFIIELNQ QTAPVRYFLF GVLFALCFSC LLAHASNLVK LVRGCVSFSW TTILCIAIGC SLLQIIIATE YVTLIMTRGM M FVNMTPCQ LNVDFVVLLV YVLFLMALTF FVSKATFCGP CENWKQHGRL IFITVLFSII IWVVWISMLL RGNPQFQRQP QW DDPVVCI ALVTNAWVFL LLYIVPELCI LYRSCRQECP LQGNACPVTA YQHSFQVENQ ELSRARDSDG AEEDSGSGSG RGR GGSENL YFQGGSGSGG DYKDDDDKDY KDDDDK

UniProtKB: G-protein coupled receptor family C group 5 member D

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Macromolecule #4: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 4 / Number of copies: 6 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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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

Concentration8.3 mg/mL
BufferpH: 7.5
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: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: OTHER / Cs: 2.73 mm / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.65 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 628867
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
FSC plot (resolution estimation)

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