Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland.
J Neurochem. 2013 Jul;126(1):29-36. doi: 10.1111/jnc.12270. Epub 2013 May 3.
2-arachidonyl glycerol (2-AG) allosterically potentiates GABA(A) receptors via a binding site located in transmembrane segment M4 of the β₂ subunit. Two amino acid residues have been described that are essential for this effect. With the aim to further describe this potential drug target, we performed a cysteine scanning of the entire M4 and part of M3. All four residues in M4 affecting the potentiation here and the two already identified residues locate to the same side of the α-helix. This side is exposed to M3, where further residues were identified. From the fact that the important residues span > 18 Å, we conclude that the hydrophobic tail of the bound 2-AG molecule must be near linear and that the site mainly locates to the inner leaflet but stretches far into the membrane. The influence of the structure of the head group of the ligand molecule on the activity of the molecule was also investigated. We present a model of 2-AG docked to the GABA(A) receptor.
2-花生四烯酸甘油（2-AG）通过位于 β₂亚基跨膜片段 M4 中的结合位点变构增强 GABA(A)受体。已经描述了两个对这种效应至关重要的氨基酸残基。为了进一步描述这个潜在的药物靶点，我们对整个 M4 及其部分 M3 进行了半胱氨酸扫描。在此增强作用中影响的 M4 中的四个残基以及已经鉴定的两个残基都位于α-螺旋的同一侧。该侧暴露于 M3，在 M3 中还鉴定了其他残基。从重要残基跨越>18 Å 的事实来看，我们得出结论，结合的 2-AG 分子的疏水性尾部必须接近线性，并且该位点主要位于内层，但延伸到膜内很远。还研究了配体分子的头基团结构对分子活性的影响。我们提出了 2-AG 与 GABA(A)受体对接的模型。
