Scholarlink

<p>The gating and function of γ-aminobutyric acid type A receptors (GABA<sub>A</sub>Rs) depend on their hetero-pentameric subunit composition, yet the rules guiding subunit selection remain unclear. We show that a conserved <i>N</i>-linked glycan in α subunits, uniquely positioned within the extracellular pore, acts as a structural constraint that limits the functional viability of α-containing assemblies. A total of 32 µs of molecular dynamics simulations of native and hypothetical non-canonical assemblies show that adding a third pore-facing glycan or placing two glycans on adjacent subunits disrupts key interactions at the β<sup>+</sup>/α<sup>–</sup> interface containing the GABA-binding site. These perturbations propagate allosterically, alter extracellular–transmembrane domain coupling, and promote deep gate closure. Systems with three pore-facing glycans consistently adopt deep-closed conformations, whereas native assemblies with two glycans preserve interfacial integrity and pore hydration. These results identify the pore-facing glycan as a structural constraint on functionally viable GABA<sub>A</sub>R architecture and gating.</p><p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

A pore-facing glycan constrains GABAA receptor subunit stoichiometry and gating behavior

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月2日

查看全文
  • Amin Akbari-Ahangar,
  • Jing Li

摘要

The gating and function of γ-aminobutyric acid type A receptors (GABAARs) depend on their hetero-pentameric subunit composition, yet the rules guiding subunit selection remain unclear. We show that a conserved N-linked glycan in α subunits, uniquely positioned within the extracellular pore, acts as a structural constraint that limits the functional viability of α-containing assemblies. A total of 32 µs of molecular dynamics simulations of native and hypothetical non-canonical assemblies show that adding a third pore-facing glycan or placing two glycans on adjacent subunits disrupts key interactions at the β+/α– interface containing the GABA-binding site. These perturbations propagate allosterically, alter extracellular–transmembrane domain coupling, and promote deep gate closure. Systems with three pore-facing glycans consistently adopt deep-closed conformations, whereas native assemblies with two glycans preserve interfacial integrity and pore hydration. These results identify the pore-facing glycan as a structural constraint on functionally viable GABAAR architecture and gating.