Selective Negative Allosteric Modulation Of Metabotropic Glutamate Receptors – A Structural Perspective of Ligands and Mutants.
Selective Negative Allosteric Modulation Of Metabotropic Glutamate Receptors – A Structural Perspective of Ligands and Mutants.
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DOI：
10.1038/srep13869
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发表时间：
2015-09-11
影响因子：
4.6
通讯作者：
Gloriam DE
中科院分区：
文献类型：
--
作者：
Harpsøe K;Isberg V;Tehan BG;Weiss D;Arsova A;Marshall FH;Bräuner-Osborne H;Gloriam DE
代谢性谷氨酸受体在中枢神经系统中具有广泛的调节功能。它们是最受关注的药物靶点之一，与几种神经系统疾病有关，许多变构调节剂已进入临床试验。然而，到目前为止，这还没有导致上市的药物，主要是因为在获得具有所需特性的亚型选择性化合物方面存在困难。最近，两种代谢性谷氨酸受体与负变构调节剂复合物的跨膜结构首次被发表。在本分析中，我们首次对所有代谢性谷氨酸受体进行了全面的结构比较，将选择性负变构调节剂和关键突变体置于受体结合位点的详细背景中。更好地了解不同的mGlu变构调节剂结合方式与选择性药理作用的关系，将对合理设计更安全的药物具有重要价值。
The metabotropic glutamate receptors have a wide range of modulatory functions in the central nervous system. They are among the most highly pursued drug targets, with relevance for several neurological diseases, and a number of allosteric modulators have entered clinical trials. However, so far this has not led to a marketed drug, largely because of the difficulties in achieving subtype-selective compounds with desired properties. Very recently the first crystal structures were published for the transmembrane domain of two metabotropic glutamate receptors in complex with negative allosteric modulators. In this analysis, we make the first comprehensive structural comparison of all metabotropic glutamate receptors, placing selective negative allosteric modulators and critical mutants into the detailed context of the receptor binding sites. A better understanding of how the different mGlu allosteric modulator binding modes relates to selective pharmacological actions will be very valuable for rational design of safer drugs.