1] Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Straße 2, Building D15, D-97080 Würzburg, Germany [2] Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Straße 2, Building D15, D-97080 Würzburg, Germany.
Nat Commun. 2014 Dec 22;5:5767. doi: 10.1038/ncomms6767.
γ-Aminobutyric acid type A and glycine receptors (GABA(A)Rs, GlyRs) are the major inhibitory neurotransmitter receptors and contribute to many synaptic functions, dysfunctions and human diseases. GABA(A)Rs are important drug targets regulated by direct interactions with the scaffolding protein gephyrin. Here we deduce the molecular basis of this interaction by chemical, biophysical and structural studies of the gephyrin-GABA(A)R α3 complex, revealing that the N-terminal region of the α3 peptide occupies the same binding site as the GlyR β subunit, whereas the C-terminal moiety, which is conserved among all synaptic GABA(A)R α subunits, engages in unique interactions. Thermodynamic dissections of the gephyrin-receptor interactions identify two residues as primary determinants for gephyrin's subunit preference. This first structural evidence for the gephyrin-mediated synaptic accumulation of GABA(A)Rs offers a framework for future investigations into the regulation of inhibitory synaptic strength and for the development of mechanistically and therapeutically relevant compounds targeting the gephyrin-GABA(A)R interaction.
γ-氨基丁酸 A 型和甘氨酸受体 (GABA(A)Rs、GlyRs) 是主要的抑制性神经递质受体，参与许多突触功能、功能障碍和人类疾病。GABA(A)Rs 是受支架蛋白 gephyrin 直接相互作用调节的重要药物靶点。通过对 gephyrin-GABA(A)R α3 复合物的化学、生物物理和结构研究，我们推导出了这种相互作用的分子基础，揭示了 α3 肽的 N 端区域占据与 GlyR β 亚基相同的结合位点，而 C 端部分在所有突触 GABA(A)R α 亚基中都保守，与独特的相互作用相关。对 gephyrin-受体相互作用的热力学剖析确定了两个残基是 gephyrin 亚基偏好的主要决定因素。这是 gephyrin 介导的 GABA(A)R 突触积累的第一个结构证据，为抑制性突触强度的调节以及针对 gephyrin-GABA(A)R 相互作用的具有机制和治疗相关性的化合物的开发提供了框架。
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