Molecular modeling and crystal structure of ERK2-hypothemycin complexes
Molecular modeling and crystal structure of ERK2-hypothemycin complexes
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DOI：
10.1016/j.jsb.2008.05.002
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发表时间：
2008-10-01
影响因子：
3
通讯作者：
Santi, Daniel V.
中科院分区：
文献类型：
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作者：
Rastelli, Giulio;Rosenfeld, Robin;Santi, Daniel V.
含有顺式烯酮的间苯二酚内酯（如hypothemycin）对Michael加成反应敏感，并且是约45种已知的Ser/Thr/Tyr蛋白激酶的有效和特异性抑制剂。这些抑制剂可逆地结合，然后与其靶激酶的ATP结合位点中的完全保守的半胱氨酸形成共价加合物。作为顺式-烯酮二苯甲环酸内酯与该激酶子集的复合物结构的范例，我们使用对接和扩展分子动力学模拟对ERK 2-下热霉素可逆和共价复合物的结构进行了建模。随后，我们确定了2.5埃分辨率的复合物的晶体结构，其与模型结构非常雅阁。结果被用来讨论结构-活性关系，并提供了一个结构模板的不可逆抑制剂，补充激酶的ATP结合位点的发展。(c)2008年爱思唯尔公司All rights reserved.
Resorcylic acid lactones containing a cis-enone-such as hypothemycin-are susceptible to Michael addition reactions and are potent and specific inhibitors of about 45 of the known Ser/Thr/Tyr protein kinases. These inhibitors bind reversibly, and then form a covalent adduct with a completely conserved cysteine in the ATP binding site of their target kinases. As a paradigm for the structures of the cis-enone resorcylic acid lactone complexes with this subset of kinases, we have modeled the structure of ERK2-hypothemycin reversible and covalent complexes using docking and extended molecular dynamics simulations. Subsequently, we determined the 2.5 angstrom resolution crystal structure of the complex that was in excellent accord with the modeled structure. The results were used to discuss structure-activity relationships, and provide a structural template for the development of irreversible inhibitors that complement the ATP binding site of kinases. (c) 2008 Elsevier Inc. All rights reserved.