Crystal structures of human HSP90α-complexed with dihydroxyphenylpyrazoles
Crystal structures of human HSP90α-complexed with dihydroxyphenylpyrazoles
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DOI：
10.1016/j.bmcl.2004.12.087
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发表时间：
2005-03-01
影响因子：
2.7
通讯作者：
Gu, XJ
中科院分区：
文献类型：
--
作者：
Kreusch, A;Han, SL;Gu, XJ
一系列二羟基苯基吡唑化合物被鉴定为一类独特的可逆 Hsp90 抑制剂。确定了与人 Hsp90 α 的 N 端 ATP 结合结构域复合的两种已鉴定化合物的晶体结构。化合物的二羟基苯环深深地嵌入腺嘌呤结合袋中，C2 羟基与 Asp93 的侧链形成直接氢键。吡唑环与 Gly97 的主链羰基、Thr184 的羟基以及水分子形成氢键，水分子存在于所有已发表的 HSP90 结构中。其中一种已鉴定的化合物 (G3130) 表现出与抑制细胞 Hsp90 功能一致的细胞活性（Her-2 降解和 Hsp70 启动子激活）。 (c) 2005 Elsevier Ltd. 保留所有权利。
A series of dihydroxyphenylpyrazole compounds were identified as a unique class of reversible Hsp90 inhibitors. The crystal structures for two of the identified compounds complexed with the N-terminal ATP binding domain of human Hsp90 alpha were determined. The dihydroxyphenyl ring of the compounds fits deeply into the adenine binding pocket with the C2 hydroxyl group forming a direct hydrogen bond with the side chain of Asp93. The pyrazole ring forms hydrogen bonds to the backbone carbonyl of Gly97, the hydroxyl group of Thr184 and to a water molecule, which is present in all of the published HSP90 structures. One of the identified compounds (G3130) demonstrated cellular activities (in Her-2 degradation and activation of Hsp70 promoter) consistent with the inhibition of cellular Hsp90 functions. (c) 2005 Elsevier Ltd. All rights reserved.