Mapping the Binding of GluN2B-Selective N-Methyl-D-aspartate Receptor Negative Allosteric Modulators
Mapping the Binding of GluN2B-Selective N-Methyl-D-aspartate Receptor Negative Allosteric Modulators
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DOI：
10.1124/mol.112.078568
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发表时间：
2012-08-01
影响因子：
3.6
通讯作者：
Traynelis, Stephen F.
中科院分区：
文献类型：
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作者：
Burger, Pieter B.;Yuan, Hongjie;Traynelis, Stephen F.
我们已经使用了最近的结构进展，在我们的理解N-甲基-D-天冬氨酸（NMDA）受体氨基末端结构域，探讨多个二芳基GluN 2B选择性负变构调节剂的结合模式之间的接口GluN 1和GluN 2B氨基末端结构域。我们发现，结合口袋内的A环的相互作用似乎在很大程度上不变的各种结构不同的配体。此外，结合位点可以容纳两个芳环之间的一系列结构多样的接头，从而提供了通过氢键供体、受体以及立体化学的变化来调节与配体结合口袋的相互作用的潜在机会。蛋白质和配体之间原子相互作用的最大多样性发生在B环中，含有电子供体和受体的官能团在口袋内提供额外的原子接触。远离结合位点的残基簇也控制配体效力、抑制程度，并且在分子动力学模拟期间显示配体诱导的运动增加。在这些残基的一些突变似乎区分结构不同的配体和提高的可能性，GluN 2B-选择性配体可以分为多个类别。这些结果应有助于促进耐受性良好的GluN 2B亚基选择性拮抗剂的发展。
We have used recent structural advances in our understanding of the N-methyl-D-aspartate (NMDA) receptor amino terminal domain to explore the binding mode of multiple diaryl GluN2B-selective negative allosteric modulators at the interface between the GluN1 and GluN2B amino-terminal domains. We found that interaction of the A ring within the binding pocket seems largely invariant for a variety of structurally distinct ligands. In addition, a range of structurally diverse linkers between the two aryl rings can be accommodated by the binding site, providing a potential opportunity to tune interactions with the ligand binding pocket via changes in hydrogen bond donors, acceptors, as well as stereochemistry. The most diversity in atomic interactions between protein and ligand occur in the B ring, with functional groups that contain electron donors and acceptors providing additional atomic contacts within the pocket. A cluster of residues distant to the binding site also control ligand potency, the degree of inhibition, and show ligand-induced increases in motion during molecular dynamics simulations. Mutations at some of these residues seem to distinguish between structurally distinct ligands and raise the possibility that GluN2B-selective ligands can be divided into multiple classes. These results should help facilitate the development of well tolerated GluN2B subunit-selective antagonists.