Structural highlights
Publication Abstract from PubMedChronic 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. A reversible allosteric inhibitor of GlyT2 for neuropathic pain without on-target side effects.,Cantwell Chater RP, Peiser-Oliver J, Pati TK, Quinn AS, Lotsaris I, Frangos ZJ, Anderson KE, Tischer AE, Williams-Noonan BJ, Aubrey KR, O'Mara ML, Michaelides M, Mohammadi SA, Cioffi CL, Vandenberg RJ, Shahsavar A Nat Commun. 2026 Feb 16. doi: 10.1038/s41467-026-69616-5. PMID:41698908[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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