Guerlet Guillaume, Taly Antoine, Prado de Carvalho Lia, Martz Adeline, Jiang Ruotian, Specht Alexandre, Le Novère Nicolas, Grutter Thomas
Department of Bioorganic Chemistry, UMR 7175 CNRS, Faculté de Pharmacie, Université Louis Pasteur, 67401 Illkirch, France.
Biochem Biophys Res Commun. 2008 Oct 24;375(3):405-9. doi: 10.1016/j.bbrc.2008.08.030. Epub 2008 Aug 19.
ATP-gated P2X receptors (P2XRs) are ligand-gated ion channels (LGICs) presumably trimeric. To date, no experimental high-resolution structures are available. Recent X-ray structure of the acid-sensing ion channel 1 (ASIC1) revealed an unexpected trimeric ion channel. Beside their quaternary structure, P2XR and ASIC1 share common membrane topologies, but no significant sequence similarity. In order to overcome this low sequence resemblance, we have developed comparative models of P2X(2)R based on secondary structure predictions using the crystal structure of ASIC1 as template. These models were constrained to be consistent with known arrangement of disulfide bridges. They agreed with cross-linking experiments and supported inter-subunit ATP-binding sites. One of our models reconciled most existing data and provides new structural insights for a plausible mechanism of gating, thus encouraging new experiments.
三磷酸腺苷门控的P2X受体（P2XRs）是推测为三聚体的配体门控离子通道（LGICs）。迄今为止，尚无实验性的高分辨率结构。最近酸敏感离子通道1（ASIC1）的X射线结构揭示了一种意想不到的三聚体离子通道。除了它们的四级结构外，P2XR和ASIC1具有共同的膜拓扑结构，但没有明显的序列相似性。为了克服这种低序列相似性，我们基于二级结构预测，以ASIC1的晶体结构为模板，开发了P2X(2)R的比较模型。这些模型受到限制，以与已知的二硫键排列一致。它们与交联实验结果相符，并支持亚基间的三磷酸腺苷结合位点。我们的一个模型整合了大多数现有数据，并为一种合理的门控机制提供了新的结构见解，从而鼓励开展新的实验。
