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- PDB-8yzk: Orphan receptor GPRC5D in complex with scFv150-18 -

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Basic information

Entry
Database: PDB / ID: 8yzk
TitleOrphan receptor GPRC5D in complex with scFv150-18
Components
  • Soluble cytochrome b562,G-protein coupled receptor family C group 5 member D
  • scFv
KeywordsMEMBRANE PROTEIN / orphan receptor / GPRC5D complex / scFv
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 speciesEscherichia coli (E. coli)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsYan, P. / Lin, X. / Xu, F.
Funding support1items
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, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jul 3, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Soluble cytochrome b562,G-protein coupled receptor family C group 5 member D
C: scFv
D: scFv
B: Soluble cytochrome b562,G-protein coupled receptor family C group 5 member D


Theoretical massNumber of molelcules
Total (without water)156,4194
Polymers156,4194
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Soluble cytochrome b562,G-protein coupled receptor family C group 5 member D / Cytochrome b-562


Mass: 47822.062 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli (E. coli), (gene. exp.) Homo sapiens (human)
Gene: cybC, GPRC5D / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P0ABE7, UniProt: Q9NZD1
#2: Antibody scFv


Mass: 30387.537 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)

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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: Complex of Orphan GPRC5D with scFv150-18 / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: OTHER / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: OTHER / Nominal defocus max: 2200 nm / Nominal defocus min: 700 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 78948 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0036623
ELECTRON MICROSCOPYf_angle_d0.7419042
ELECTRON MICROSCOPYf_dihedral_angle_d4.897914
ELECTRON MICROSCOPYf_chiral_restr0.0441059
ELECTRON MICROSCOPYf_plane_restr0.0061128

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