Mutations designed to destabilize the receptor-bound conformation increase MICA-NKG2D association rate and affinity.
作者： Candice S. E. Lengyel , Lindsey J. Willis , Patrick Mann , David Baker , Tanja Kortemme
关键词: Mutant 、 Surface plasmon resonance 、 Mica 、 Receptor–ligand kinetics 、 Entropy (order and disorder) 、 Protein structure 、 Wild type 、 Kinetics 、 Chemistry 、 Biochemistry 、 Biophysics
摘要: MICA is a major histocompatibility complex-like protein that undergoes structural transition from disorder to order upon binding its immunoreceptor, NKG2D. We redesigned the disordered region of with RosettaDesign increase NKG2D binding. Mutations stabilize this were expected association kinetics without changing dissociation kinetics, affinity interaction, and reduce entropy loss mutants stable in solution, they amenable surface plasmon resonance evaluation thermodynamics. Several bound enhanced affinity, kinetic changes primarily observed during association, thermodynamic as expected. However, none 15 combinations mutations predicted receptor-bound conformation whereas all 10 be destabilized increased on-rates. Five these had affinities by 0.9-1.8 kcal/mol over wild type one three non-contacting substitutions. Therefore, case, designed mildly destabilize affinity.
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