9IMA

Cryo-EM structure for the GPRC5D complexed with Talquetamab Fab

Summary for 9IMA

• Entry DOI: 10.2210/pdb9ima/pdb
• EMDB information: 60686
• Descriptor: Talquetamab Fab (anti-GPRC5D) Heavy chain, Talquetamab Fab (anti-GPRC5D) Light chain, G-protein coupled receptor family C group 5 member D, ... (4 entities in total)
• Functional Keywords: talquetamab, class c gpcr, multiple myeloma, bispecific antibody, membrane protein-immune system complex, membrane protein/immune system
• Biological source: Mus musculus; More
• Total number of polymer chains: 4
• Total formula weight: 130203.43

Authors

Jeong, J.,Shin, J.,Park, J.,Cho, Y. (deposition date: 2024-07-02, release date: 2024-09-11, Last modification date: 2024-11-20)

Primary citation

Jeong, J.,Park, J.,Young Mo, G.,Shin, J.,Cho, Y.
Structural Basis for the Recognition of GPRC5D by Talquetamab, a Bispecific Antibody for Multiple Myeloma.
J.Mol.Biol., 436:168748-168748, 2024

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 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.

PubMed: 39181182
DOI: 10.1016/j.jmb.2024.168748

Experimental method

ELECTRON MICROSCOPY (2.65 Å)