TARGET FLEXIBILITY IN MOLECULAR RECOGNITION
Wei Gu, Michael Kofler, Iris Antes, Christian Freund, Volkhard Helms, J. Andrew Mccammon · 2014
Recognition of proline-rich sequences plays an important role for the assembly of multi-protein complexes during the course of eukaryotic signal transduction and is mediated by a set of protein folds that share characteristic features. The GYF (glycine-tyrosine-phenylalanine) domain is known as a member of the super-family of recognition domains for proline-rich sequences. Recent studies on the complexation of the CD2BP2-GYF domain with CD2 peptides showed that the peptide adopts an extended conformation and forms a polyproline type II helix involving residues Pro4- Pro7 [1]. R/K/GxxPPGxR/K is the key signature for the peptides that bind to the GYF domain [2]. In our combined theoretical and experimental study, we show that the peptides adopt a polyproline II helical conformation in the unbound form as well as in the complex. By molecular dynamics simulations we identify a novel binding mode for the G8W mutant and the wild-type peptide (shifted by one proline in register). In contrast, the conformation of the peptide mutant H9M remains close to the experimentally derived wild-type GYF-peptide complex. Possible functional implications of this