9HUG
Inward-open structure of human glycine transporter 2 in substrate-free state
Summary for 9HUG
| Entry DOI | 10.2210/pdb9hug/pdb |
| EMDB information | 52409 52410 52411 |
| Descriptor | Sodium- and chloride-dependent glycine transporter 2, CHOLESTEROL, CHLORIDE ION (3 entities in total) |
| Functional Keywords | transport protein, slc6a5, neurotransmitter/sodium symporter, sodium- and chloride-dependent glycine transporter 2, membrane protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 69784.78 |
| Authors | Cantwell Chater, R.P.,Peiser-Oliver, J.,Pati, T.K.,Quinn, A.S.,Lotsaris, I.,Frangos, Z.J.,Anderson, K.E.,Tischer, A.E.,Williams-Noonan, B.J.,Aubrey, K.R.,O Mara, M.L.,Michaelides, M.,Mohammadi, S.A.,Cioffi, C.L.,Vandenberg, R.J.,Shahsavar, A. (deposition date: 2024-12-22, release date: 2026-02-25) |
| Primary citation | Cantwell Chater, R.P.,Peiser-Oliver, J.,Pati, T.K.,Quinn, A.S.,Lotsaris, I.,Frangos, Z.J.,Anderson, K.E.,Tischer, A.E.,Williams-Noonan, B.J.,Aubrey, K.R.,O'Mara, M.L.,Michaelides, M.,Mohammadi, S.A.,Cioffi, C.L.,Vandenberg, R.J.,Shahsavar, A. A reversible allosteric inhibitor of GlyT2 for neuropathic pain without on-target side effects. Nat Commun, 2026 Cited by PubMed Abstract: Chronic neuropathic pain, caused by nerve damage or disease, is increasing in prevalence, but current treatments are ineffective and over-reliant on opioids. The neuronal glycine transporter, GlyT2, regulates inhibitory glycinergic neurotransmission and represents a promising target for new analgesics. However, most GlyT2 inhibitors cause significant side effects, in part due to irreversible inhibition at analgesic doses. Here we develop a reversible inhibitor of GlyT2, RPI-GLYT2-82, and identify its binding site by determining cryo-EM structures of human GlyT2. We capture three fundamental conformational states of GlyT2 in the substrate-free state, and bound to either glycine, RPI-GLYT2-82 or the pseudo-irreversible inhibitor ORG25543. We demonstrate that RPI-GLYT2-82 dissociates from GlyT2 faster than ORG25543, providing analgesia in mouse neuropathic pain models without on-target side-effects or addiction liability. Our data provide a mechanistic understanding of allosteric inhibition of glycine transport, enabling structure-based design of non-opioid analgesics. PubMed: 41698908DOI: 10.1038/s41467-026-69616-5 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.97 Å) |
Structure validation
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