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Title
Japanese:Exploring the selectivity of inhibitor complexes with Bcl-2 and Bcl-XL: A molecular dynamics simulation approach 
English:Exploring the selectivity of inhibitor complexes with Bcl-2 and Bcl-XL: A molecular dynamics simulation approach 
Author
Japanese: 和久井 直樹, 吉野 龍ノ介, 安尾 信明, 大上 雅史, 関嶋 政和.  
English: Wakui, N., Yoshino, R., Yasuo, N., Ohue, M., Sekijima, M..  
Language English 
Journal/Book name
Japanese:Journal of Molecular Graphics and Modelling 
English:Journal of Molecular Graphics and Modelling 
Volume, Number, Page Vol. 79        pp. 166-174
Published date Jan. 2018 
Publisher
Japanese: 
English: 
Conference name
Japanese: 
English: 
Conference site
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English: 
Official URL http://www.scopus.com/inward/record.url?eid=2-s2.0-85035768007&partnerID=MN8TOARS
 
DOI https://doi.org/10.1016/j.jmgm.2017.11.011
Abstract B-cell lymphoma 2 (Bcl-2) family proteins are potential drug targets in cancer and have a relatively flat and flexible binding site. ABT-199 is one of the most promising selective Bcl-2 inhibitors, and A-1155463 selectively inhibits Bcl-XL. Although the amino acid sequences of the binding sites of these two inhibitors are similar, the inhibitors selectively bind the target protein. In order to determine the origin of the selectivity of these inhibitors, we conducted molecular dynamics simulations using protein-inhibitor modeling. We confirmed that ASP103 of Bcl-2 is a key residue and that hydrogen bonding between ASP103 and ABT-199 confers the Bcl-2 selectivity of this inhibitor. For Bcl-XL selectivity, the secondary structure of α-helix 3 is a key factor. PHE105, SER106, and LEU108 in the loose α-helix 3 interact with A-1155463 to confer Bcl-XL selectivity. These findings provide important insights into the molecular mechanisms of selective inhibitors of Bcl-2 family proteins.

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