Evolution-guided discovery and recoding of allosteric pathway specificity determinants in psychoactive bioamine receptors.

ABSTRACT: G protein-coupled receptors for dopamine and serotonin control signaling pathways targeted by many psychoactive drugs. A puzzle is how receptors with similar functions and nearly identical binding site structures, such as D2 dopamine receptors and 5-HT2A serotonin receptors, could evolve a mechanism that discriminates stringently in their cellular responses between endogenous neurotransmitters. We used the Difference Evolutionary Trace (Difference-ET) and residue-swapping to uncover two distinct sets of specificity-determining sequence positions. One at the ligand-binding pocket determines the relative affinities for these two ligands, and a distinct, surprising set of positions outside the binding site determines whether a bound ligand can trigger the conformational rearrangement leading

SUBMITTER: Rodriguez GJ 

PROVIDER: S-EPMC2867884 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature