9cq4
From Proteopedia
G115 gamma delta TCR/CD3 complex bound by OKT3 Fab
Structural highlights
DiseaseCD3D_HUMAN Defects in CD3D are a cause of severe combined immunodeficiency autosomal recessive T-cell-negative/B-cell-positive/NK-cell-positive (T(-)B(+)NK(+) SCID) [MIM:608971. A form of severe combined immunodeficiency (SCID), a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients present in infancy recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development.[1] FunctionCD3D_HUMAN The CD3 complex mediates signal transduction. Publication Abstract from PubMedThe T-cell receptor (TCR)/CD3 complex plays an essential role in the immune response and is a key player in cancer immunotherapies. There are two classes of TCR/CD3 complexes, defined by their TCR chain usage (alphabeta or gammadelta). Recently reported structures have revealed the organization of the alphabeta TCR/CD3 complex, but similar studies regarding the gammadelta TCR/CD3 complex have lagged behind. Here, we report cryoelectron microscopy (cryoEM) structural analysis of two gammadelta TCRs, G115 (Vgamma9 Vdelta2) and 9C2 (Vgamma5 Vdelta1), in complex with CD3 subunits. Our results show that the overall subunit organization of the gammadelta TCR/CD3 complexes is similar to alphabeta TCRs. However, both gammadelta TCRs display highly mobile extracellular domains (ECDs), unlike alphabeta TCRs, which have TCR ECDs that are rigidly coupled to its transmembrane (TM) domains. We corroborate this finding in cells by demonstrating that a gammadelta T-cell specific antibody can bind a site that would be inaccessible in the more rigid alphabeta TCR/CD3 complex. Furthermore, we observed that the Vgamma5 Vdelta1 complex forms a TCR gamma5 chain-mediated dimeric species whereby two TCR/CD3 complexes are assembled. Collectively, these data shed light on gammadelta TCR/CD3 complex formation and may aid the design of gammadelta TCR-based therapies. Structural characterization of two gammadelta TCR/CD3 complexes.,Hoque M, Grigg JB, Ramlall T, Jones J, McGoldrick LL, Lin JC, Olson WC, Smith E, Franklin MC, Zhang T, Saotome K Nat Commun. 2025 Jan 2;16(1):318. doi: 10.1038/s41467-024-55467-5. PMID:39747888[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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