Molecular Modeling And Rational Design Of Noncovalent Halogenmidline Horizontal Ellipsisoxygenmidline Horizontal Ellipsishydrogen Motif At The Complex Interface Of Egfr Kinase Domain With Ralt Peptide

Epidermal growth factor receptor (EGFR) of ErbB tyrosine kinase is involved in the pathogenesis and progression of diverse carcinoma types. The receptor-associated late transducer (RALT) is an endogenous feedback inhibitor of EGFR by competitively disrupting the kinase dimerization event through its fragment 1 (fgt1). In the present study, the intermolecular interaction of EGFR kinase domain with RALT fgt1 was investigated to rationally design a noncovalent halogenMIDLINE HORIZONTAL ELLIPSISoxygenMIDLINE HORIZONTAL ELLIPSIShydrogen motif across the interaction interface, which consists of a halogen bond between the kinase and fgt1-derived peptide as well as a hydrogen bond in the kinase that share a common carbonyl oxygen acceptor. The halogen types and substitution positions were systematically optimized to determine their best combination involved in the noncovalent motif. A cooperative effect was observed between the halogen bond and hydrogen bond, suggesting that the whole noncovalent motif is a holonomic system that can work together to promote the kinase-peptide binding.