Molecular mechanisms of the protein-protein interaction–regulated binding specificity of basic-region leucine zipper transcription factors

  • Qing Li
  • Le Xiong
  • Jun GaoEmail author
  • Hong-Yu ZhangEmail author
Original Paper


It is well known that the DNA-binding specificity of transcription factors (TFs) is influenced by protein-protein interactions (PPIs). However, the underlying molecular mechanisms remain largely unknown. In this work, we adopted the cAMP-response element-binding protein (CREB) of the basic leucine zipper (bZIP) TF family as a model system, and a workflow of combined bioinformatics and molecular modeling analysis of protein-DNA interaction was tested. First, the multiple sequence alignment and SDPsite method were used to find potential bZIP family binding specificity determining positions (SDPs) within the protein-protein interaction region. Second, the mutation system was analyzed using molecular dynamics simulation. Molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) free energy calculations confirmed the enhancement of the binding affinity of the mutation, which was in agreement with experimental results. The root mean square fluctuation (RMSF) and hydrogen bonding changes suggested an open and close protein dimerization process after the system was mutated, which resulted in the change of the hydrogen bonding of the protein-DNA interface and a slight conformational change. We believe that this work will contribute to understanding the protein-protein interaction–regulated binding specificity of bZIP transcription factors.


Transcription factors Binding specificity Protein-protein interactions Specificity determining positions Molecular dynamics simulation 


Funding information

This work was supported by the National Key R&D Program of China (Grant No. 2017YFB0203405), National Natural Science Foundation of China (Nos. 21873034, 31670779), Fundamental Research for the Central Universities (Project 2662018JC027), and Huazhong Agricultural University Scientific & Technological Self Innovation Foundation (Program No. 2015RC008).

Supplementary material

894_2019_4138_MOESM1_ESM.pdf (149 kb)
ESM 1 (PDF 148 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Hubei Key Laboratory of Agricultural Bioinformatics, College of InformaticsHuazhong Agricultural UniversityWuhanPeople’s Republic of China

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