9KM8

Cryo-EM structure of Xenopus tropicalis glycine transporter 2 in complex with VVZ149

This is a non-PDB format compatible entry.

Summary for 9KM8

• Entry DOI: 10.2210/pdb9km8/pdb
• EMDB information: 62425
• Descriptor: Transporter, 4-butoxy-~{N}-[[4-(dimethylamino)oxan-4-yl]methyl]-3,5-dimethoxy-benzamide, CHOLESTEROL (3 entities in total)
• Functional Keywords: glyt2; protein structure, membrane protein
• Biological source: Xenopus tropicalis (tropical clawed frog)
• Total number of polymer chains: 1
• Total formula weight: 67444.51

Authors

Wang, Y.,Zhao, Y. (deposition date: 2024-11-15, release date: 2025-11-19, Last modification date: 2025-12-10)

Primary citation

Wang, Y.,Su, J.,Zhao, J.,Li, R.,Bai, Q.,Song, H.,Meng, Y.,Ma, Q.,Zhao, Y.
Mechanisms of transport and analgesic compounds recognition by glycine transporter 2.
Proc.Natl.Acad.Sci.USA, 122:e2506722122-e2506722122, 2025

PubMed 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.

PubMed: 41284875
DOI: 10.1073/pnas.2506722122

Experimental method

ELECTRON MICROSCOPY (3.5 Å)