Molecular modeling of the interactions of glutamate carboxypeptidase II with its potent NAAG-based inhibitors.
Molecular modeling of the interactions of glutamate carboxypeptidase II with its potent NAAG-based inhibitors.
复制标题
谷氨酸羧肽酶 II 与其有效的基于 NAAG 的抑制剂相互作用的分子模型。
DOI：
10.1021/jm010561g
复制
发表时间：
2002
影响因子：
7.3
通讯作者：
Kozikowski,AlanP
中科院分区：
文献类型：
--
作者：
Rong,Suo-Bao;Zhang,Jiazhong;Neale,JosephH;Wroblewski,JardaT;Wang,Shaomeng;Kozikowski,AlanP
Glutamate carboxypeptidase II (GCPII, NAALADase, or NAAG peptidase) is a catalytic zinc metallopeptidase. Its extracellular domain hydrolyzes the abundant neuropeptide,N-acetyl-l-aspartyl-l-glutamate (NAAG), to produceN-acetylaspartate and glutamate following the synaptic release of this transmitter. Thus, GCPII influences the extracellular concentrations of both glutamate and NAAG. NAAG activates group II metabotropic glutamate receptors, and activation of this receptor has been found to protect against anoxia-induced excitotoxic nerve cell death. In contrast, high levels of glutamate can be neurotoxic. Thus, GCPII is a potential therapeutic target for the reduction of excitotoxic levels of glutamate and enhancement of extracellular NAAG. To explore the structural basis of the interaction between GCPII and its inhibitors, we modeled the three-dimensional structure of the GCPII extracellular domain using a homology modeling approach. On the basis of the GCPII model, the structures of GCPII in complex with its potent inhibitors 2-(phosphonomethyl)pentanedioic acid (PMPA) and 4,4‘-phosphinicobis(butane-1,3-dicarboxylic acid) (PBDA) were built by a computational docking method. The model of GCPII mainly consists of two α/β/α sandwiches, between which two zinc ions are quadrivalently coordinated by the His379-Asp389-Asp455-H2O and the Asp389-Glu427-His555-H2O clusters, respectively. The ligand binding pocket is situated between these two sandwiches and is comprised of two subpockets: one is a surface-exposed highly positively charged subpocket; the other is a buried hydrophobic subpocket. The positively charged subpocket can accommodate the pharmacophore groups of inhibitor molecules (PMPA and PBDA) through the coordination of Zn2+with their phosphorus functionality and hydrogen-bonding interactions with Arg536, Arg538, and Ser456 (or Asn521), while the hydrophobic subpocket is engaged in hydrophobic and hydrogen-bonding interactions with the nonpharmacophore groups of PBDA. The predicted binding mode is consistent with the experimental data obtained from site-directed mutagenesis. On the basis of the predicted interaction mode, our structure-based design has led to a series of highly potent GCPII inhibitors.
