9LNZ

Crystal Structure of Intracellular B30.2 Domain of VpBTN3 in Complex with HMBPP-08

Summary for 9LNZ

• Entry DOI: 10.2210/pdb9lnz/pdb
• Descriptor: Butyrophylin 3, SULFATE ION, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: butyrophilin, signaling protein
• Biological source: Vicugna pacos (alpaca)
• Total number of polymer chains: 2
• Total formula weight: 54688.75

Authors

Yang, Y.Y.,Yi, S.M.,Zhang, M.T.,Chen, C.-C.,Guo, R.-T. (deposition date: 2025-01-22, release date: 2025-05-21, Last modification date: 2025-09-03)

Primary citation

Liu, C.,Yi, S.,Zhang, M.,Chen, C.C.,Liu, Y.,Zhang, Z.,Guo, R.T.,Yang, Y.
Molecular glue binding behavior of phosphoantigens to alpaca butyrophilins.
J.Biol.Chem., 301:108555-108555, 2025

PubMed Abstract: Vγ9Vδ2 T cells that respond to phosphoantigen (pAg) function as crucial sentinels of the immune system to eradicate pathogen-infected cells and tumor cells. Alpaca (Vicugna pacos) is the first nonprimate species identified to possess the pAg-reactive Vγ9Vδ2 T cell subset. However, the molecular mechanism accounting for the pAg recognition of alpaca Vγ9Vδ2 T cells remains unclear. Here, we report the crystal structures of alpaca butyrophilin 3 (VpBTN3) B30.2 domain in complex with the exogenous pAg analog, HMBPP-08, which is a valuable tool for studying the mechanism of butyrophilin-dependent Vγ9Vδ2 T cell activation, and the endogenous pAg analogue, dimethylallyl (S)-thiolodiphosphate (DMASPP). We elucidated that the function of pAgs is governed by their structural differences. Notably, DMASPP acts as a molecular glue in the interaction between the intracellular B30.2 domains of heterologous butyrophilins in alpaca and human. Interestingly, although HMBPP-08 has stronger affinity than DMASPP to VpBTN3 B30.2 domain, HMBPP-08 did not promote heterologous VpBTNs interaction. These findings establish a novel theoretical framework elucidating the mechanisms of Vγ9Vδ2 T cell activation and demonstrate the conserved evolutionary mechanisms underlying cross-species immune adaptation.

PubMed: 40294650
DOI: 10.1016/j.jbc.2025.108555

Experimental method

X-RAY DIFFRACTION (1.93 Å)