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TitleConformational transitions and allosteric modulation in a heteromeric glycine receptor.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 1363, Year 2023
Publish dateMar 13, 2023
AuthorsEric Gibbs / Emily Klemm / David Seiferth / Arvind Kumar / Serban L Ilca / Philip C Biggin / Sudha Chakrapani /
PubMed AbstractGlycine Receptors (GlyRs) provide inhibitory neuronal input in the spinal cord and brainstem, which is critical for muscle coordination and sensory perception. Synaptic GlyRs are a heteromeric ...Glycine Receptors (GlyRs) provide inhibitory neuronal input in the spinal cord and brainstem, which is critical for muscle coordination and sensory perception. Synaptic GlyRs are a heteromeric assembly of α and β subunits. Here we present cryo-EM structures of full-length zebrafish α1βGlyR in the presence of an antagonist (strychnine), agonist (glycine), or agonist with a positive allosteric modulator (glycine/ivermectin). Each structure shows a distinct pore conformation with varying degrees of asymmetry. Molecular dynamic simulations found the structures were in a closed (strychnine) and desensitized states (glycine and glycine/ivermectin). Ivermectin binds at all five interfaces, but in a distinct binding pose at the β-α interface. Subunit-specific features were sufficient to solve structures without a fiduciary marker and to confirm the 4α:1β stoichiometry recently observed. We also report features of the extracellular and intracellular domains. Together, our results show distinct compositional and conformational properties of αβGlyR and provide a framework for further study of this physiologically important channel.
External linksNat Commun / PubMed:36914669 / PubMed Central
MethodsEM (single particle)
Resolution3.0 Å
Structure data

29019

8fe1

EMDB-29019, PDB-8fe1:
Alpha1/BetaB Heteromeric Glycine Receptor in 1 mM Glycine 20 uM Ivermectin State
Method: EM (single particle) / Resolution: 3.0 Å

Chemicals

ChemComp-GLY:
GLYCINE

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

ChemComp-IVM:
(2aE,4E,5'S,6S,6'R,7S,8E,11R,13R,15S,17aR,20R,20aR,20bS)-6'-[(2S)-butan-2-yl]-20,20b-dihydroxy-5',6,8,19-tetramethyl-17 / antiparasitic*YM

ChemComp-PX4:
1,2-DIMYRISTOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / DMPC, phospholipid*YM

ChemComp-PLM:
PALMITIC ACID

ChemComp-D10:
DECANE

Source
  • danio rerio (zebrafish)
KeywordsMEMBRANE PROTEIN / Glycine / Channel / Ivermectin / Pentameric

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