8YZK

Orphan receptor GPRC5D in complex with scFv150-18

Summary for 8YZK

• Entry DOI: 10.2210/pdb8yzk/pdb
• EMDB information: 39696
• Descriptor: Soluble cytochrome b562,G-protein coupled receptor family C group 5 member D, scFv (2 entities in total)
• Functional Keywords: orphan receptor, gprc5d complex, scfv, membrane protein
• Biological source: Escherichia coli; More
• Total number of polymer chains: 4
• Total formula weight: 156419.20

Authors

Yan, P.,Lin, X.,Xu, F. (deposition date: 2024-04-07, release date: 2024-07-03, Last modification date: 2025-07-23)

Primary citation

Yan, P.,Lin, X.,Wu, L.,Xu, L.,Li, F.,Liu, J.,Xu, F.
The binding mechanism of an anti-multiple myeloma antibody to the human GPRC5D homodimer.
Nat Commun, 15:5255-5255, 2024

PubMed 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, 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.

PubMed: 38898050
DOI: 10.1038/s41467-024-49625-y

Experimental method

ELECTRON MICROSCOPY (3.4 Å)