9JQP

Cryo-EM structure of the HMBPP-primed BTN3A1-BTN3A2-BTN2A1 in complex with agonist antibody TH001

Summary for 9JQP

• Entry DOI: 10.2210/pdb9jqp/pdb
• EMDB information: 61732
• Descriptor: Butyrophilin subfamily 3 member A1, Butyrophilin subfamily 3 member A2, Butyrophilin subfamily 2 member A1, ... (6 entities in total)
• Functional Keywords: antibody, agonist, phosphoantigen, butyrophilin, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 7
• Total formula weight: 204366.13

Authors

Zhang, M.,Wang, Y.Q.,Xiao, J.Y. (deposition date: 2024-09-28, release date: 2025-06-18, Last modification date: 2025-07-23)

Primary citation

Zhang, M.,Wang, Y.,Cai, N.,Qu, Y.,Ma, X.,Xue, J.,Chen, X.,Zhang, X.,Xiao, J.,Zhang, Y.
Structures of butyrophilin multimers reveal a plier-like mechanism for V gamma 9V delta 2 T cell receptor activation.
Immunity, 58:1660-, 2025

PubMed Abstract: Vγ9Vδ2 T cells, the major circulating human γδ T cell subset, respond to infections and tumors by recognizing phosphoantigens (pAgs) via transmembrane butyrophilins (BTN3A1, BTN3A2, and BTN2A1). Here, using cryoelectron microscopy, we resolved the structures of BTN multimers bound to the microbial pAg HMBPP alone and in complex with the T cell receptor (TCR). These structures reveal that BTN3A1 and BTN2A1 cooperate to sense pAgs through their intracellular B30.2 domains, whereas BTN3A2 and BTN2A1 interact extracellularly. TCR engagement triggers its conformational changes, allowing BTN2A1 to bind the Vγ9 chain laterally and BTN3A2 to interact apically with the Vδ2 chain's germline-encoded regions and CDR3 motif, as well as the Vγ9 CDR3. Our study uncovers a "plier-like gripping" mechanism, where BTN multimers bridge the TCR surface to drive activation. These findings establish a structural foundation for γδ T cell-targeted immunotherapies distinct from αβ T cell strategies reliant on major-histocompatibility-complex-mediated antigen presentation.

PubMed: 40505658
DOI: 10.1016/j.immuni.2025.05.011

Experimental method

ELECTRON MICROSCOPY (3.34 Å)