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- EMDB-39696: Orphan receptor GPRC5D in complex with scFv150-18 -

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Basic information

Entry
Database: EMDB / ID: EMD-39696
TitleOrphan receptor GPRC5D in complex with scFv150-18
Map data
Sample
  • Complex: Complex of Orphan GPRC5D with scFv150-18
    • Protein or peptide: Soluble cytochrome b562,G-protein coupled receptor family C group 5 member D
    • Protein or peptide: scFv
Keywordsorphan receptor / GPRC5D complex / scFv / MEMBRANE PROTEIN
Function / homology
Function and homology information


protein kinase activator activity / G protein-coupled receptor activity / electron transport chain / periplasmic space / electron transfer activity / receptor complex / iron ion binding / intracellular membrane-bounded organelle / heme binding / extracellular exosome / plasma membrane
Similarity search - Function
GPCR family 3, C-terminal / 7 transmembrane sweet-taste receptor of 3 GCPR / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562
Similarity search - Domain/homology
Soluble cytochrome b562 / G-protein coupled receptor family C group 5 member D
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsYan P / Lin X / Xu F
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2024
Title: The binding mechanism of an anti-multiple myeloma antibody to the human GPRC5D homodimer.
Authors: Pengfei Yan / Xi Lin / Lijie Wu / Lu Xu / Fei Li / Junlin Liu / Fei Xu /
Abstract: GPRC5D is an atypical Class C orphan G protein-coupled receptor. Its high expression on the surface of multiple myeloma cells has rendered it an attractive target for therapeutic interventions, ...GPRC5D is an atypical Class C orphan G protein-coupled receptor. Its high expression on the surface of multiple myeloma cells has rendered it an attractive target for therapeutic interventions, including monoclonal antibodies, CAR-T cells, and T-cell engagers. Despite its therapeutic potential, the insufficient understanding regarding of the receptor's structure and antibody recognition mechanism has impeded the progress of effective therapeutic development. Here, we present the structure of GPRC5D in complex with a preclinical-stage single-chain antibody (scFv). Our structural analysis reveals that the GPRC5D presents a close resemblance to the typical Class C GPCRs in the transmembrane region. We identify a distinct head-to-head homodimer arrangement and interface mainly involving TM4, setting it apart from other Class C homo- or hetero-dimers. Furthermore, we elucidate the binding site engaging a sizable extracellular domain on GPRC5D for scFv recognition. These insights not only unveil the distinctive dimer organization of this unconventional Class C GPCR but also hold the potential to advance drug development targeting GPRC5D for the treatment of multiple myeloma.
History
DepositionApr 7, 2024-
Header (metadata) releaseJul 3, 2024-
Map releaseJul 3, 2024-
UpdateJul 3, 2024-
Current statusJul 3, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_39696.png

Downloads & links

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Map

FileDownload / File: emd_39696.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.832 Å
Density
Contour LevelBy AUTHOR: 0.08
Minimum - Maximum-0.0018723968 - 2.156652
Average (Standard dev.)0.0016623363 (±0.027976833)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 212.992 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_39696_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_39696_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Complex of Orphan GPRC5D with scFv150-18

EntireName: Complex of Orphan GPRC5D with scFv150-18
Components
  • Complex: Complex of Orphan GPRC5D with scFv150-18
    • Protein or peptide: Soluble cytochrome b562,G-protein coupled receptor family C group 5 member D
    • Protein or peptide: scFv

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Supramolecule #1: Complex of Orphan GPRC5D with scFv150-18

SupramoleculeName: Complex of Orphan GPRC5D with scFv150-18 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Soluble cytochrome b562,G-protein coupled receptor family C group...

MacromoleculeName: Soluble cytochrome b562,G-protein coupled receptor family C group 5 member D
type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 47.822062 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKTIIALSYI FCLVFADYKD DDDAGRAADL EDNWETLNDN LKVIEKADNA AQVKDALTKM RAAALDAQKA TPPKLEDKSP DSPEMKDFR HGFDILVGQI DDALKLANEG KVKEAQAAAE QLKTTRNAYI QKYLMYKDCI ESTGDYFLLC DAEGPWGIIL E SLAILGIV ...String:
MKTIIALSYI FCLVFADYKD DDDAGRAADL EDNWETLNDN LKVIEKADNA AQVKDALTKM RAAALDAQKA TPPKLEDKSP DSPEMKDFR HGFDILVGQI DDALKLANEG KVKEAQAAAE QLKTTRNAYI QKYLMYKDCI ESTGDYFLLC DAEGPWGIIL E SLAILGIV VTILLLLAFL FLMRKIQDCS QWNVLPTQLL FLLSVLGLFG LAFAFIIELN QQTAPVRYFL FGVLFALCFS CL LAHASNL VKLVRGCVSF SWTTILCIAI GCSLLQIIIA TEYVTLIMTR GMMFVNMTPC QLNVDFVVLL VYVLFLMALT FFV SKATFC GPCENWKQHG RLIFITVLFS IIIWVVWISM LLRGNPQFQR QPQWDDPVVC IALVTNAWVF LLLYIVPELC ILYR SEFLE VLFQGPHHHH HHHHHH

UniProtKB: Soluble cytochrome b562, G-protein coupled receptor family C group 5 member D

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Macromolecule #2: scFv

MacromoleculeName: scFv / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 30.387537 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MLLVNQSHQG FNKEHTSKMV SAIVLYVLLA AAAHSAFASS ELTQDPAVSV ALGQTVRITC QGDSLRSYYA SWYQQKPGQA PVLVIYGKN NRPSGIPDRF SGSSSGNTAS LTITGAQAED EADYYCNSRD SSGNPPVVFG GGTKLTVLGS RGGGGSGGGG S GGGGSLEM ...String:
MLLVNQSHQG FNKEHTSKMV SAIVLYVLLA AAAHSAFASS ELTQDPAVSV ALGQTVRITC QGDSLRSYYA SWYQQKPGQA PVLVIYGKN NRPSGIPDRF SGSSSGNTAS LTITGAQAED EADYYCNSRD SSGNPPVVFG GGTKLTVLGS RGGGGSGGGG S GGGGSLEM AQVQLVESGG GLVHPGGSLR LSCAASGFTF RSHSMNWVRQ APGKGLEWVS SISSDSTYTY YADSVKGRFT IS RDNAKNS LYLQMNSLRA EDTAVYYCAR SGGQWKYYDY WGQGTLVTVS S

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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

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: OTHER
Electron opticsIllumination mode: OTHER / Imaging mode: OTHER / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.7000000000000001 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 78948
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER

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