Common and selective molecular determinants involved in metabotopic glutamate receptor agonist activity
Common and selective molecular determinants involved in metabotopic glutamate receptor agonist activity
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DOI：
10.1021/jm010323l
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发表时间：
2002-07-18
影响因子：
7.3
通讯作者：
Acher, FC
中科院分区：
文献类型：
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作者：
Bertrand, HO;Bessis, AS;Acher, FC
代谢型谷氨酸受体 (mGluR) 的几种有效的组选择性激动剂已对接在二叶酸胞外结构域闭合构象中的 mGlu1,2,4R 结合位点上。选择使君子酸和(S)-3,5-二羟基苯基甘氨酸(3,5-DHPG)用于mGlu1R，选择二羧基环丙基甘氨酸(DCG-IV)、LY354740，选择(S)-4-羧基苯基甘氨酸(4CPG)用于mGlu2R，以及(S)-2-氨基-4-膦丁酸(AP4)， 1-氨基环戊烷-1,3,4-三羧酸 (ACPT-1)、(S)-4-膦酰基苯基甘氨酸 (PPG) 用于 mGlu4R。该模型显示了甘氨酸部分（α-氨基和α-酸性功能）的保守结合模式以及远端酸性功能的基团特异性结合。最好的激动剂可以优化与结合域两个叶的相互作用。配体周围的叶间连接也被描述，并参与稳定氨基末端结构域的闭合形式。总而言之，对接模型支持以下观点：闭合状态的稳定是 mGluR 激动剂激活的关键步骤。
Several potent and group selective agonists of metabotropic glutamate receptors (mGluRs) have been docked at mGlu1,2,4R binding sites in the closed conformation of the bilobate extracellular domain. Quisqualic acid and (S)-3,5-dihydroxyphenylglycine (3,5-DHPG) were selected for mGlu1R, dicarboxycyclopropylglycine (DCG-IV), LY354740, (S)-4-carboxyphenylglycine (4CPG) for mGlu2R, and (S)-2-amino-4-phosphonobutyric acid (AP4), 1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-1), (S)-4-phosphonophenylglycine (PPG) for mGlu4R. The models show a conserved binding pattern for the glycine moiety (a-amino and a-acidic functions) and group specific bindings for the distal acidic function. The best agonists allow optimized interaction with both lobes of the binding domain. Interlobe connections around the ligand are also described and participate in stabilizing the closed form of the amino-terminal domain. Altogether, the docking models support the proposal that the stabilization of a closed state represents a key step in agonist activation of mGluRs.