Engineering a GPCR-ligand pair that simulates the activation of D(2L) by Dopamine.

ABSTRACT: In the past decade, engineered G-protein-coupled receptors activated solely by synthetic ligands (RASSLs) have been implemented as a new means to study neurotransmission, which is controlled by G-protein-coupled receptors in vitro and in vivo. In this study, we report an engineered dopamine receptor D(2L) F390(6.52)W, which is the first identified RASSL for the dopamine receptor family. The mutant receptor is characterized by a disrupted ligand binding and complete loss of efficacy for the endogenous ligand, dopamine, which is putatively due to a sterically induced perturbation of H-bonding with conserved serine residues in TM5. Based on this model, we rationally developed an aminoindane-derived set of agonists. Because these agonists forgo analogous H-bonding functionalities, their bindin

SUBMITTER: Tschammer N 

PROVIDER: S-EPMC3368624 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature