Making ERRFI1-Derived Peptides ‘Bindable’ to the Allosteric Dimerization Interface of Breast Cancer ERBB3 Kinase by Adding a Nonbonded Interaction System

• DOI: 10.1007/s10989-021-10298-6
• Publication Date: 2021-10-13T15:57:51Z
• Authors: Chenghong Ji; Jianmin Zhuang; Yizhou Jiang; Jiangang Mu; Longhai Lin; Yide Chen
• Keywords: ERBB3; Protein kinase domain; ErbB

The ERBB3 is a member of human receptor tyrosine kinase ErbB family involved in various cellular processes, which has been recognized as a new and promising druggable target of breast cancer and some other gynecological tumors. The ERRFI1 protein is a natural negative regulator of ErbB signaling and has been found to inactivate ERBB3 kinase activity by directly disrupting the kinase dimerization with its ErbB-binding region (EBR). The ERRFI1 EBR domain contains two functional segments 1 and 2 as well as a flexible loop (FL) linker between the two segments, which can only weakly interact with ERBB3 kinase domain to form a reversible, transient encounter complex. Here, we demonstrated that the binding affinity and recognition specificity of ERBB3 interaction with ERRFI1 FL peptides can be improved essentially by just adding a designed nonbonded interaction system across the kinase–peptide complex interface. The nonbonded system consists of one or two hydrogen bonds as well as a double aromatic stacking. High-level theoretical calculations indicated that these nonbonded forces can work together to confer considerable stability and specificity to the complex, thus making ERRFI1-derived peptides ‘bindable’ to ERBB3 kinase domain. The theoretical analysis was further substantiated by calorimetric study, which revealed that the designed nonbonded system can improve the kinase–peptide binding free energy by − 5 to – 20 kJ/mol with different arrangements of its nonbonded forces.