title: The molecular basis of IGF-II/IGF2R recognition: a combined molecular dynamics simulation, free-energy calculation and computational alanine scanning study.
abstract: Insulin-like growth factor-II (IGF-II) is a key regulator of cell growth, survival, migration and differentiation, and is thus pivotal in many cancers. An individual with a high IGF-II level is at high risk of developing cancer, whereas IGF2R is implicated as being important in tumor suppression. Thus, uncovering the essence of the IGF-II/IGF2R interaction is very important to understanding the origin of the tumor-suppressing effect of IGF2R. In this study, in order to investigate the interaction of the IGF-II/IGF2R complex and to characterize the binding hot spots of this interaction, a 10 ns molecular dynamics simulation combined with MM-PBSA/MM-GBSA computations and computational alanine scanning was performed on the IGF-II/IGF2R complex. From the results of the free-energy decomposition and the computational alanine scanning calculation, we identified the key residues in the IGF-II/IGF-2R interaction. The results from the calculation were consistent with reported experimental mutagenesis studies. The information on the interaction of IGF-II and IGF2R obtained is vital for understanding how the structure of IGF2R influences the function of IGF-II in growth and development. This study will also lead to new opportunities to develop molecular probes that can assist in diagnostic screening, and even novel approaches to controlling tumor development.
authors.affiliation: State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Guo
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Wang
authors.forename: Huijun
authors.initials: H
authors.lastname: Sun
authors.forename: Huanxiang
authors.initials: H
authors.lastname: Liu
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Yao
mesh_terms: D000409:Alanine / Q000032:analysis*; D001665:Binding Sites; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D020836:Protein Structure, Quaternary; D017527:Receptor, IGF Type 2 / Q000737:chemistry / Q000378:metabolism*
chemical_list: C035170:IGF2 protein, human; D017527:Receptor, IGF Type 2; D007335:Insulin-Like Growth Factor II; D000409:Alanine