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The binding mechanism of an anti-multiple myeloma antibody to the human GPRC5D homodimer

Author

Listed:
  • Pengfei Yan

    (ShanghaiTech University
    ShanghaiTech University)

  • Xi Lin

    (ShanghaiTech University)

  • Lijie Wu

    (ShanghaiTech University)

  • Lu Xu

    (ShanghaiTech University
    JiKang Therapeutics)

  • Fei Li

    (ShanghaiTech University)

  • Junlin Liu

    (ShanghaiTech University)

  • Fei Xu

    (ShanghaiTech University
    ShanghaiTech University
    Shanghai Clinical Research and Trial Center)

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.

Suggested Citation

  • Pengfei Yan & Xi Lin & Lijie Wu & Lu Xu & Fei Li & Junlin Liu & Fei Xu, 2024. "The binding mechanism of an anti-multiple myeloma antibody to the human GPRC5D homodimer," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49625-y
    DOI: 10.1038/s41467-024-49625-y
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