Interaction between IGFBP7 and insulin: a theoretical and experimental study.
Insulin-like growth factor binding protein 7 (IGFBP7) can bind to insulin with high affinity which inhibits the early steps of insulin action. Lack of recognition mechanism impairs our understanding of insulin regulation before it binds to insulin receptor. Here we combine computational simulations with experimental methods to investigate the interaction between IGFBP7 and insulin. Molecular dynamics simulations indicated that His200 and Arg198 in IGFBP7 were key residues. Verified by experimental data, the interaction remained strong in single mutation systems R198E and H200F but became weak in double mutation system R198E-H200F relative to that in wild-type IGFBP7. The results and methods in present study could be adopted in future research of discovery of drugs by disrupting protein-protein interactions in insulin signaling. Nevertheless, the accuracy, reproducibility, and costs of free-energy calculation are still problems that need to be addressed before computational methods can become standard binding prediction tools in discovery pipelines.
Department of Pathology, School of Medicine, Zhejiang University, Hangzhou 310058, P. R. China.|Department of Respiratory Medicine, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, P.R. China.
Wenjing
W
Ruan
Soft Matter Research Center and Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China.
Zhengzhong
Z
Kang
Department of Pathology, School of Medicine, Zhejiang University, Hangzhou 310058, P. R. China.
Youzhao
Y
Li
Soft Matter Research Center and Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China.
Tianyang
T
Sun
Department of Pathology, School of Medicine, Zhejiang University, Hangzhou 310058, P. R. China.
Lipei
L
Wang
Soft Matter Research Center and Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China.
Lijun
L
Liang
Department of Pathology, School of Medicine, Zhejiang University, Hangzhou 310058, P. R. China.
Maode
M
Lai
Soft Matter Research Center and Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China.
Tao
T
Wu
D001665:Binding Sites; D015153:Blotting, Western; D006801:Humans; D007328:Insulin / Q000737:chemistry / Q000378:metabolism*; D018969:Insulin-Like Growth Factor Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D055672:Static Electricity; D013816:Thermodynamics
D007328:Insulin; D018969:Insulin-Like Growth Factor Binding Proteins; C102529:insulin-like growth factor binding protein-related protein 1