PNAS, 24 November, 2025, DOI：https://doi.org/10.1038/s41467-025-65388-6

Mechanisms of transport and analgesic compounds recognition by glycine transporter 2

Yuhang Wang, Jiawei Su, Jun Zhao, Renjie Li, Qinru Bai, Hongyi Song, Yufei Meng, Qiao Ma, and Yan Zhao

Abstract

Glycine transporter 2 (GlyT2) regulates inhibitory glycinergic neurotransmission, and its inhibition potentiates glycinergic signaling, which is a promising strategy for managing neuropathic pain. This study presents high-resolution structures of GlyT2 in its apo state and in complexes with the substrate glycine, analgesic inhibitors, captured in three functional states: outward-facing, occluded, and inward-facing. The glycine-bound structure reveals the binding mode of the substrate, Na⁺ and Cl⁻. Specifically, we identified the Na3 binding site, offering fundamental insights into Na⁺/Cl⁻ coupled substrate binding and conformational changes. Moreover, we clearly elucidate a previously unseen allosteric binding pocket for the lipid-based oleoyl-D-lysine, which acts as a wedge to stabilize GlyT2 in the outward-facing conformation and prevents its transition. Furthermore, the complex structures with small compounds ALX1393, opiranserin, and ORG25543 reveal their competitive and allosteric inhibition mechanisms. Overall, our study provides a solid foundation for understanding glycine reuptake mechanisms and developing effective and safer analgesic agents.

文章链接：https://www.pnas.org/doi/full/10.1073/pnas.2506722122