Tschammer N, Doerfler M, Hübner H, Gmeiner P (2010)
Publication Type: Journal article, Original article
Publication year: 2010
Original Authors: Tschammer N., Dorfler M., Hubner H., Gmeiner P.
Publisher: American Chemical Society
Book Volume: 1
Pages Range: 25-35
Journal Issue: 1
DOI: 10.1021/cn900001b
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 F390W, 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 binding energy does not depend on the respective interactions. Binding affinity and potency were optimized by ligand modifications bearing molecular appendages that obviously interact with a secondary recognition site provided by four hydrophobic residues in TM2 and TM3. Thus, the ferrocenyl carboxamide 5b (FAUC 185) was identified as a synthetic agonist that is able to stimulate the mutant receptor in a manner similar to that by which endogenous dopamine activates the D wild-type receptor. The engineered dopamine receptor D F390 W in combination with FAUC 185 (5b) provides a new tool to probe GPCR functions selectively in specific cell populations in vitro and in vivo. © 2009 American Chemical Society.
APA:
Tschammer, N., Doerfler, M., Hübner, H., & Gmeiner, P. (2010). Engineering a GPCR-ligand pair that simulates the activation of D 2L by dopamine. ACS Chemical Neuroscience, 1(1), 25-35. https://doi.org/10.1021/cn900001b
MLA:
Tschammer, Nuska, et al. "Engineering a GPCR-ligand pair that simulates the activation of D 2L by dopamine." ACS Chemical Neuroscience 1.1 (2010): 25-35.
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