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Title | Structural Basis for the Recognition of GPRC5D by Talquetamab, a Bispecific Antibody for Multiple Myeloma. |
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Journal, issue, pages | J Mol Biol, Vol. 436, Issue 20, Page 168748, Year 2024 |
Publish date | Oct 15, 2024 |
Authors | Jihong Jeong / Junhyeon Park / Geun Young Mo / Jinwoo Shin / Yunje Cho / |
PubMed 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. |
External links | J Mol Biol / PubMed:39181182 |
Methods | EM (single particle) |
Resolution | 2.65 Å |
Structure data | EMDB-60686, PDB-9ima: |
Chemicals | ChemComp-CLR: |
Source |
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Keywords | MEMBRANE PROTEIN/IMMUNE SYSTEM / Talquetamab / class C GPCR / multiple myeloma / bispecific antibody / MEMBRANE PROTEIN-IMMUNE SYSTEM complex |