9KM7
Cryo-EM structure of glycine transporter 2 in complex with ORG25543
This is a non-PDB format compatible entry.
Summary for 9KM7
| Entry DOI | 10.2210/pdb9km7/pdb |
| EMDB information | 62424 |
| Descriptor | Transporter, ~{N}-[[1-(dimethylamino)cyclopentyl]methyl]-3,5-dimethoxy-4-phenylmethoxy-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 | 67462.53 |
| Authors | |
| 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 Cited by 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: 41284875DOI: 10.1073/pnas.2506722122 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.8 Å) |
Structure validation
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