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Architecture and assembly mechanism of native glycine receptors

Abstract

Glycine receptors (GlyRs) are pentameric, ‘Cys-loop’ receptors that form chloride-permeable channels and mediate fast inhibitory signaling throughout the central nervous system1,2. In the spinal cord and brainstem, GlyRs regulate locomotion and cause movement disorders when mutated2,3. However, the stoichiometry of native GlyRs and the mechanism by which they are assembled remain unclear, despite extensive investigation4–8. Here we report near-atomic resolution structures of native GlyRs from porcine spinal cord and brainstem, revealing the first structural insight into heteromeric receptors and their predominant stoichiometry of 4 α subunits:1 β subunit. Within the heteromeric pentamer, the β(+)/α(-) interface adopts a structure that is distinct from the α(+)/α(-) and α(+)/β(-) interfaces. Furthermore, the β subunit harbors a unique phenylalanine residue that resides within the pore and disrupts the canonical picrotoxin site. These results explain why inclusion of the β subunit breaks receptor symmetry and alters ion channel pharmacology. We also find incomplete receptor complexes and, by elucidating their structures, reveal the architectures of partially assembled α trimers and α tetramers for the first time.

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Correspondence to Eric Gouaux.

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This file contains Supplementary Figs 1-2. Supplementary Fig. 1 shows the original gel and original results for the western blots and Supplementary Fig. 2 displays amino acid sequence alignment, secondary structure and posttranslational modifications for porcine GlyR α1 (GlyRA1) and β (GlyRB) subunits.

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Zhu, H., Gouaux, E. Architecture and assembly mechanism of native glycine receptors. Nature (2021). https://doi.org/10.1038/s41586-021-04022-z

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