Kaczor Agnieszka A, Kijkowska-Murak Urszula A, Matosiuk Dariusz
Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Faculty of Pharmacy, Medical University of Lublin, 6 Staszica Str., 20081 Lublin, Poland.
J Med Chem. 2008 Jul 10;51(13):3765-76. doi: 10.1021/jm7011694. Epub 2008 Jun 10.
There is numerous experimental and conceptual proof that the extracellular portion of ionotropic glutamate receptors (iGluRs), i.e., N-terminal domain (NTD) and ligand-binding core (LBD), exhibits 2-fold rotational symmetry and thus dimer of dimers architecture. However, the problem of the structure and symmetry of the transmembrane channel forming region of iGluRs has not been solved yet. According to the most common approach, glutamate ion channels possess 4-fold symmetry, similar to homologous potassium channels. This results in a symmetry mismatch between the extracellular fragment of the receptor and its transmembrane domain. To overcome the above discrepancies in iGluR symmetry, homology modeling was applied to propose an alternative model of GluR5 channel transmembrane region. Because of modification of M3 helix structure, as indicated by experimental results, the obtained model is generally characterized by 2-fold rotational symmetry. As a validation of the applied methodology, IEM-1754 was docked to the obtained GluR5 receptor transmembrane fragment model. However, because there are no affinity values available for IEM-1754, the applied methodology was additionally validated by building of NMDA receptor transmembrane region model and its evaluation in the docking of dextrorphan, (+)-MK-801, and IEM-1925. Moreover, the NMDA and GluR5 channel models are consistent with all available experimental data, including the latest single-particle electron microscopy images of iGluRs.
有大量实验和概念性证据表明，离子型谷氨酸受体（iGluRs）的细胞外部分，即N端结构域（NTD）和配体结合核心（LBD），呈现出2倍旋转对称性，因此具有二聚体的二聚体结构。然而，iGluRs跨膜通道形成区域的结构和对称性问题尚未得到解决。根据最常见的方法，谷氨酸离子通道具有4倍对称性，类似于同源钾通道。这导致受体的细胞外片段与其跨膜结构域之间存在对称性不匹配。为了克服iGluR对称性中的上述差异，应用同源建模来提出GluR5通道跨膜区域的替代模型。如实验结果所示，由于M3螺旋结构的改变，所获得的模型通常具有2倍旋转对称性。作为对所应用方法的验证，将IEM-1754对接至所获得的GluR5受体跨膜片段模型。然而,由于没有IEM-1754的亲和力值，通过构建NMDA受体跨膜区域模型并在右啡烷、(+)-MK-801和IEM-1925的对接中对其进行评估，对所应用的方法进行了额外验证。此外，NMDA和GluR5通道模型与所有可用的实验数据一致，包括iGluRs的最新单颗粒电子显微镜图像。
