X-ray Crystal Structure of Phosphodiesterase 2 in Complex with a Highly Selective, Nanomolar Inhibitor Reveals a Binding-Induced Pocket Important for Selectivity
X-ray Crystal Structure of Phosphodiesterase 2 in Complex with a Highly Selective, Nanomolar Inhibitor Reveals a Binding-Induced Pocket Important for Selectivity
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DOI：
10.1021/ja404449g
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发表时间：
2013-08-14
影响因子：
15
通讯作者：
Huang, Qiang
中科院分区：
文献类型：
--
作者：
Zhu, Jian;Yang, Qjqi;Huang, Qiang
为了更好地了解人类磷酸二酯酶家族（PDEs 1-11）抑制剂选择性的结构起源，在这里，我们报告了PDE 2与高选择性纳摩尔抑制剂（BAY 60 -7550）复合物的X射线晶体结构，分辨率为1.9埃，以及apo PDE 2的结构，分辨率为2.0埃。晶体结构表明，抑制剂结合到PDE 2的活性位点，不仅使用保守的谷氨酰胺开关机制的底物结合，但也结合诱导，疏水口袋，这是以前没有报道。通过分子对接进行的计算机模拟亲和力分析表明，与该口袋结合的抑制剂对结合亲和力有显著贡献，从而提高了抑制剂对PDE 2的选择性。我们的研究结果突出了一个基于结构的设计策略，利用潜在的结合诱导的口袋，以实现更高的选择性在PDE抑制剂的发展。
To better understand the structural origins of inhibitor selectivity of human phosphodieasterase families (PDEs 1-11), here we report the X-ray crystal structure of PDE2 in complex with a highly selective, nanomolar inhibitor (BAY60-7550) at 1.9 angstrom resolution, and the structure of apo PDE2 at 2.0 angstrom resolution. The crystal structures reveal that the inhibitor binds to the PDE2 active site by using not only the conserved glutamine-switch mechanism for substrate binding, but also a binding-induced, hydrophobic pocket that was not reported previously. In silico affinity profiling by molecular docking indicates that the inhibitor binding to this pocket contributes significantly to the binding affinity and thereby improves the inhibitor selectivity for PDE2. Our results highlight a structure-based design strategy that exploits the potential binding-induced pockets to achieve higher selectivity in the PDE inhibitor development.