Water-mediated conformational preselection mechanism in substrate binding cooperativity to protein kinase A.

ABSTRACT: Substrate binding cooperativity in protein kinase A (PKA) seems to involve allosteric coupling between the two binding sites. It received significant attention, but its molecular basis still remains not entirely clear. Based on long molecular dynamics of PKA and its complexes, we characterized an allosteric pathway that links ATP binding to the redistribution of states adopted by a protein substrate positioning segment in favor of those that warrant correct binding. We demonstrate that the cooperativity mechanism critically depends on the presence of water in two distinct, buried hydration sites. One holds just a single water molecule, which acts as a switchable hydrogen bond bridge along the allosteric pathway. The second, filled with partially disordered solvent, is essential for providi

SUBMITTER: Setny P 

PROVIDER: S-EPMC5899460 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature