Structural characterization of the GSK-3β active site using selective and non-selective ATP-mimetic inhibitors
Structural characterization of the GSK-3β active site using selective and non-selective ATP-mimetic inhibitors
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DOI：
10.1016/j.jmb.2003.08.031
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发表时间：
2003-10-17
影响因子：
5.6
通讯作者：
Flocco, M
中科院分区：
文献类型：
--
作者：
Bertrand, JA;Thieffine, S;Flocco, M
GSK-3beta是一种具有多种细胞靶点的调节丝氨酸/苏氨酸激酶。因此，gsk -3 β的选择性小分子抑制剂可能具有多种治疗用途，包括治疗神经退行性疾病、II型糖尿病和癌症。为了表征GSK-3beta的活性位点，我们测定了未磷酸化GSK-3beta与选择性和非选择性atp模拟抑制剂复合物的晶体结构。对抑制剂与gsk -3 β在结构中的相互作用的分析揭示了这种酶如何容纳许多不同的分子支架。此外，在Thr1.38附近发现了一个保守的水分子，可以在抑制剂结合中发挥功能作用。最后，选择性和非选择性抑制剂相互作用的比较突出了ATP结合位点边缘的残基，这些残基可用于获得抑制剂的选择性。从这些结构中获得的信息为设计第二代gsk -3 β抑制剂提供了一条有希望的途径。(C) 2003 Elsevier Ltd.版权所有。
GSK-3beta is a regulatory serine/threonine kinase with a plethora of cellular targets. Consequently, selective small molecule inhibitors of GSK-3beta may have a variety of therapeutic uses including the treatment of neurodegenerative diseases, type II diabetes and cancer. In order to characterize the active site of GSK-3beta, we determined crystal structures of unphosphorylated GSK-3beta in complex with selective and non-selective ATP-mimetic inhibitors. Analysis of the inhibitors' interactions with GSK-3beta in the structures reveals how the enzyme can accommodate a number of diverse molecular scaffolds. In addition, a conserved water molecule near Thr1.38 is identified that can serve a functional role in inhibitor binding. Finally, a comparison of the interactions made by selective and non-selective inhibitors highlights residues on the edge of the ATP binding-site that can be used to obtain inhibitor selectivity. Information gained from these structures provides a promising route for the design of second-generation GSK-3beta inhibitors. (C) 2003 Elsevier Ltd. All rights reserved.