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TitleMechanism of human α3β GlyR regulation by intracellular M3/M4 loop phosphorylation and 2,6-di-tert-butylphenol interaction.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 5242, Year 2025
Publish dateJun 5, 2025
AuthorsXiaofen Liu / Malgorzata Krezel / Weiwei Wang /
PubMed Abstractα3β glycine receptor (GlyR) is a subtype of GlyRs that belongs to the Cys-loop receptor superfamily. It is highly expressed in the spinal dorsal horn where sensory information is integrated. Under ...α3β glycine receptor (GlyR) is a subtype of GlyRs that belongs to the Cys-loop receptor superfamily. It is highly expressed in the spinal dorsal horn where sensory information is integrated. Under inflammatory conditions, the large unstructured intracellular M3/M4 loops of the α3 subunit are phosphorylated through the prostaglandin E2 (PGE) pathway, inhibiting ion conduction, and resulting in elevated pain sensation. A small molecule analgesic analog, 2,6-di-tert-butylphenol (2,6-DTBP) potentiates phosphorylated α3β GlyR through unclear mechanisms and relieves pain. Combining cryo-Electron Microscopy (cryo-EM) structures and single molecule Förster resonance energy transfer (smFRET) experiments, we show compaction of M3/M4 loop towards the ion conduction pore upon phosphorylation and further by 2,6-DTBP binding, which in turn modulates function through changing pore conformations and local electrostatics. We show that simultaneous interactions with the M3/M4 loop and the transmembrane domain (TM) is necessary for the potentiation of heteromeric α3β GlyR by 2,6-DTBP, while TM interaction alone is sufficient to potentiate homomeric α3 GlyR, explaining the mystery of why 2,6-DTBP potentiates only phosphorylated α3β GlyR. These findings show how post-translational modification of the unstructured intracellular M3/M4 loop may regulate Cys-loop receptor function, providing new perspectives in pain control and other pharmaceutical development targeting GlyRs and other Cys-loop receptors.
External linksNat Commun / PubMed:40473619 / PubMed Central
MethodsEM (single particle)
Resolution3.6 - 3.84 Å
Structure data

44754

9boy

EMDB-44754, PDB-9boy:
Cryo-EM structure of human Glycine Receptor apha3-beta heteromer with glycine in nanodisc
Method: EM (single particle) / Resolution: 3.81 Å

44755

9boz

EMDB-44755, PDB-9boz:
Cryo-EM structure of human Glycine Receptor alpha3-beta heteromer in presence of glycine
Method: EM (single particle) / Resolution: 3.84 Å

44763

9bp7

EMDB-44763, PDB-9bp7:
Cryo-EM structure of human heteromeric Glycine Receptor alpha3S346E-beta in presence of glycine and 2,6-DTBP
Method: EM (single particle) / Resolution: 3.6 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-GLY:
GLYCINE

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / glycine receptor subunit alpha-3 / glycine receptor subunit beta / Green fluorescent protein

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