9bbc | pdb_00009bbc
TCR GDN detergent micelle
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) initiates T-lymphocyte activation, but mechanistic questions remain( 1-4 ). Here, we present cryogenic electron microscopy structures for the unliganded and human leukocyte antigen (HLA)-bound human TCR-CD3 complex in nanodiscs that provide a native-like lipid environment. Distinct from the "open and extended" conformation seen in detergent( 5-8 ), the unliganded TCR-CD3 in nanodiscs adopts two related "closed and compacted" conformations that represent its physiologic resting state in vivo . By contrast, the HLA-bound complex adopts the open and extended conformation, and conformation-locking disulfide mutants show that ectodomain opening is necessary for maximal ligand-dependent T-cell activation. Together, these results reveal allosteric conformational change during TCR activation and highlight the importance of native-like lipid environments for membrane protein structure determination. The resting and ligand-bound states of the membrane-embedded human T-cell receptor-CD3 complex.,Notti RQ, Yi F, Heissel S, Bush MW, Molvi Z, Das P, Molina H, Klebanoff CA, Walz T bioRxiv [Preprint]. 2024 Sep 20:2023.08.22.554360. doi: , 10.1101/2023.08.22.554360. PMID:37662363[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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