Insights into structure and function of SHIP2-SH2: homology modeling, docking, and molecular dynamics study

Journal of Chemical Biology

Uzma Saqib¹  Mohammad Imran Siddiqi¹ 

[1] Molecular and Structural Biology Division, Central Drug Research Institute, CSIR India, Lucknow, 226 001 India

关键词: Docking;    Molecular dynamics;    Shc;    SHIP2-SH2;    Type 2 diabetes;   

DOI  :  10.1007/s12154-011-0057-7

学科分类：分子生物学，细胞生物学和基因

来源: Springer

【 摘 要 】

SRC homology 2 (SH2)-containing inositol 5′-phosphatase protein (SHIP2) is a potential target for type 2 diabetes. Its ability to dephosphorylate the lipid messenger phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3], important for insulin signaling, makes it an important target against type 2 diabetes. The insulin-induced SHIP2 interaction with Shc is very important for the membrane localization and functioning of SHIP2. There is a bidentate relationship between the two proteins where two domains each from SHIP2 and Shc are involved in mutual binding. However in the present study, the SHIP2-SH2 domain binding with the phosphorylated tyrosine 317 on the collagen-homology (CH) domain of Shc, has been studied due to the indispensability of this interaction in SHIP2 localization. In the absence of the crystal structure of SHIP2-SH2, its structural model was developed followed by tracking its molecular interactions with Shc through molecular docking and dynamics studies. This study revealed much about the structural interactions between the SHIP2-SH2 and Shc-CH. Finally, docking study of a nonpeptide inhibitor into the SHIP2-SH2 domain further confirmed the structural interactions involved in ligand binding and also proposed the inhibitor as a major starting point against SHIP2-SH2 inhibition. The insights gained from the current study should prove useful in the design of more potent inhibitors against type 2 diabetes.

【 授权许可】

Unknown