Evolution-guided discovery and recoding of allosteric pathway specificity determinants in psychoactive bioamine receptors.
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 to G protein activation. Thus one site specifies affinity while the other encodes a filter for efficacy. These findings demonstrate that allosteric pathways linking distant interactions via alternate conformational states enforce specificity independently of the ligand-binding site, such that either one may be rationally rekeyed to different ligands. The conversion of a dopamine receptor effectively into a serotonin receptor illustrates the plasticity of GPCR signaling during evolution, or in pathological states, and suggests new approaches to drug discovery, targeting both classes of sites.
Rodriguez
Gustavo J
GJ
Verna and Marrs Mclean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Yao
Rong
R
Lichtarge
Olivier
O
Wensel
Theodore G
TG
D000494:Allosteric Regulation / Q000235:genetics*; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D019143:Evolution, Molecular; D005453:Fluorescence; D006801:Humans; D008958:Models, Molecular; D016296:Mutagenesis; D011487:Protein Conformation; D011619:Psychotropic Drugs / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*
D011619:Psychotropic Drugs; D043562:Receptors, G-Protein-Coupled
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