Paramo Teresa, Brown Patricia M G E, Musgaard Maria, Bowie Derek, Biggin Philip C
Department of Biochemistry, University of Oxford, Oxford, United Kingdom.
Integrated Program in Neurosciences, McGill University, Montréal, Québec, Canada.
Biophys J. 2017 Nov 21;113(10):2173-2177. doi: 10.1016/j.bpj.2017.08.047. Epub 2017 Sep 19.
Kainate receptors require the presence of external ions for gating. Most work thus far has been performed on homomeric GluK2 but, in vivo, kainate receptors are likely heterotetramers. Agonists bind to the ligand-binding domain (LBD) which is arranged as a dimer of dimers as exemplified in homomeric structures, but no high-resolution structure currently exists of heteromeric kainate receptors. In a full-length heterotetramer, the LBDs could potentially be arranged either as a GluK2 homomer alongside a GluK5 homomer or as two GluK2/K5 heterodimers. We have constructed models of the LBD dimers based on the GluK2 LBD crystal structures and investigated their stability with molecular dynamics simulations. We have then used the models to make predictions about the functional behavior of the full-length GluK2/K5 receptor, which we confirmed via electrophysiological recordings. A key prediction and observation is that lithium ions bind to the dimer interface of GluK2/K5 heteromers and slow their desensitization.
海人酸受体的门控需要外部离子的存在。迄今为止，大多数研究都是在同聚体GluK2上进行的，但在体内，海人酸受体可能是异源四聚体。激动剂与配体结合结构域（LBD）结合，该结构域以二聚体的二聚体形式排列，如同聚体结构中所示，但目前尚无异源海人酸受体的高分辨率结构。在全长异源四聚体中，LBDs可能要么与GluK5同聚体一起排列成GluK2同聚体，要么排列成两个GluK2/K5异源二聚体。我们基于GluK2 LBD晶体结构构建了LBD二聚体模型，并通过分子动力学模拟研究了它们的稳定性。然后，我们使用这些模型对全长GluK2/K5受体的功能行为进行预测，并通过电生理记录进行了证实。一个关键的预测和观察结果是，锂离子与GluK2/K5异源二聚体的二聚体界面结合并减缓其脱敏过程。
