标题: | Core Site-Moiety Maps Reveal Inhibitors and Binding Mechanisms of Orthologous Proteins by Screening Compound Libraries |
作者: | Hsu, Kai-Cheng Cheng, Wen-Chi Chen, Yen-Fu Wang, Hung-Jung Li, Ling-Ting Wang, Wen-Ching Yang, Jinn-Moon 生物科技学系 生物资讯及系统生物研究所 Department of Biological Science and Technology Institude of Bioinformatics and Systems Biology |
公开日期: | 29-二月-2012 |
摘要: | Members of protein families often share conserved structural subsites for interaction with chemically similar moieties despite low sequence identity. We propose a core site-moiety map of multiple proteins (called CoreSiMMap) to discover inhibitors and mechanisms by profiling subsite-moiety interactions of immense screening compounds. The consensus anchor, the subsite-moiety interactions with statistical significance, of a CoreSiMMap can be regarded as a "hot spot" that represents the conserved binding environments involved in biological functions. Here, we derive the CoreSiMMap with six consensus anchors and identify six inhibitors (IC50 < 8.0 mu M) of shikimate kinases (SKs) of Mycobacterium tuberculosis and Helicobacter pylori from the NCI database (236,962 compounds). Studies of site-directed mutagenesis and analogues reveal that these conserved interacting residues and moieties contribute to pocket-moiety interaction spots and biological functions. These results reveal that our multi-target screening strategy and the CoreSiMMap can increase the accuracy of screening in the identification of novel inhibitors and subsite-moiety environments for elucidating the binding mechanisms of targets. |
URI: | http://dx.doi.org/e32142 http://hdl.handle.net/11536/16135 |
ISSN: | 1932-6203 |
DOI: | e32142 |
期刊: | PLOS ONE |
Volume: | 7 |
Issue: | 2 |
结束页: | |
显示于类别: | Articles |
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