2025-11-25 中国科学院(CAS)
Binding modes of GlyT2 with substrate glycine and various analgesic inhibitors (Image by ZHAO Yan’s group)
<関連情報>
- https://english.cas.cn/newsroom/research_news/life/202512/t20251202_1134374.shtml
- https://www.pnas.org/doi/10.1073/pnas.2506722122
グリシントランスポーター2による輸送と鎮痛剤認識のメカニズム Mechanisms of transport and analgesic compounds recognition by glycine transporter 2
Yuhang Wang, Jiawei Su, Jun Zhao, +5 , and Yan Zhao
Proceedings of the National Academy of Sciences Published:November 24, 2025
DOI:https://doi.org/10.1073/pnas.2506722122
Significance
Chronic pain is a significant health challenge due to the limited efficacy and severe side effects of current treatments. Glycine transporter 2 (GlyT2) is a key regulator of inhibitory neurotransmission in the spinal cord and brainstem, emerging as a promising target for novel analgesics. Our study provides critical insights into the transport mechanisms of GlyT2 and the binding actions of various analgesics. We determined high-resolution structures of GlyT2 in multiple conformations, revealing a unique third sodium binding site and distinct binding sites for different inhibitors, including a lipid-based inhibitor. These findings advance our understanding of neurotransmitter transporters and provide a structural basis for designing more effective and safer pain relief therapies, addressing a critical unmet need in pain management.
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.
