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TitleA reversible allosteric inhibitor of GlyT2 for neuropathic pain without on-target side effects.
Journal, issue, pagesNat Commun, Year 2026
Publish dateFeb 16, 2026
AuthorsRyan P Cantwell Chater / Julian Peiser-Oliver / Tanmay K Pati / Ada S Quinn / Irina Lotsaris / Zachary J Frangos / Kristen E Anderson / Anna E Tischer / Billy J Williams-Noonan / Karin R Aubrey / Megan L O'Mara / Michael Michaelides / Sarasa A Mohammadi / Christopher L Cioffi / Robert J Vandenberg / Azadeh Shahsavar /
PubMed AbstractChronic 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, ...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.
External linksNat Commun / PubMed:41698908
MethodsEM (single particle)
Resolution2.49 - 3.02 Å
Structure data

52409

9hue

EMDB-52409, PDB-9hue:
Outward-open structure of human glycine transporter 2 bound to allosteric inhibitor ORG25543
Method: EM (single particle) / Resolution: 2.49 Å

52410

9huf

EMDB-52410, PDB-9huf:
Outward-open structure of human glycine transporter 2 bound to allosteric inhibitor RPI-GLYT2-82
Method: EM (single particle) / Resolution: 2.79 Å

52411

9hug

EMDB-52411, PDB-9hug:
Inward-open structure of human glycine transporter 2 in substrate-free state
Method: EM (single particle) / Resolution: 2.97 Å

53509

9r1h

EMDB-53509, PDB-9r1h:
Inward-occluded structure of human glycine transporter 2 bound to substrate glycine
Method: EM (single particle) / Resolution: 3.02 Å

Chemicals

PDB-1ef1:
CRYSTAL STRUCTURE OF THE MOESIN FERM DOMAIN/TAIL DOMAIN COMPLEX

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-CLR:
CHOLESTEROL

ChemComp-CL:
Unknown entry

ChemComp-NA:
Unknown entry

ChemComp-HOH:
WATER

PDB-1ixx:
CRYSTAL STRUCTURE OF COAGULATION FACTORS IX/X-BINDING PROTEIN (IX/X-BP) FROM VENOM OF HABU SNAKE WITH A HETERODIMER OF C-TYPE LECTIN DOMAINS

ChemComp-GLY:
GLYCINE

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Transport protein / SLC6A5 / neurotransmitter/sodium symporter / Sodium- and chloride-dependent glycine transporter 2

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