Flavonoid allosteric modulation of mutated visual rhodopsin associated with retinitis pigmentosa

Abstract

Dietary flavonoids exhibit many biologically-relevant functions and can potentially have beneficial effects in the treatment of pathological conditions. In spite of its well known antioxidant properties, scarce structural information is available on the interaction of flavonoids with membrane receptors. Advances in the structural biology of a specific class of membrane receptors, the G protein-coupled receptors, have significantly increased our understanding of drug action and paved the way for developing improved therapeutic approaches. We have analyzed the effect of the flavonoid quercetin on the conformation, stability and function of the G protein-coupled receptor rhodopsin, and the G90V mutant associated with the retinal degenerative disease retinitis pigmentosa. By using a combination of experimental and computational methods, we suggest that quercetin can act as an allosteric modulator of opsin regenerated with 9-cis-retinal and more importantly, that this binding has a positive effect on the stability and conformational properties of the G90V mutant associated with retinitis pigmentosa. These results open new possibilities to use quercetin and other flavonoids, in combination with specific retinoids like 9-cis-retinal, for the treatment of retinal degeneration associated with retinitis pigmentosa. Moreover, the use of flavonoids as allosteric modulators may also be applicable to other members of the G protein-coupled receptors superfamily.

The Retinoid and Non-Retinoid Ligands of the Rod Visual G Protein-Coupled Receptor

“…Direct interaction of flavonoids with opsin and their stabilizing effect due to increased structural rigidity was also reported for cyaniding-3-glucoside by using 1 H NMR [29]. Enhanced stability and regeneration with 9-cis-retinal were also noted for the adRP-associated unstable mutant G90V [27]. The opsin-stabilizing effect of flavonoids could also be related to the enhanced opsin self-association facilitated by flavonoids.…”

“…Topological analysis of multiple GPCR structures using computational algorithms revealed a high diversity of the allosteric binding sites as the ligands could locate within the ECLs, between TM helices and within the ICLs (see Figure 4 and [23]). Similarly to other GPCRs [24,25], allosteric modulation of rhodopsin also was suggested [26][27][28][29].…”

“…Indeed, rhodopsin assembled into oligomers within the ROS membranes is more stable than dissociated monomers caused upon solubilization with detergent [61,62]. In addition, the binding of flavonoids did not prevent pigment regeneration with 9-cis-retinal but rather resulted in increased rate of retinal binding to opsin by about two-fold [20,27]. A similar effect of increased regeneration rates was also observed for polyphenols such as anthocyanin and cyanidin-3-glucoside [26,63].…”

“…(see Figure 4 and [23]). Similarly to other GPCRs [24,25], allosteric modulation of rhodopsin also was suggested [26][27][28][29]. Structural analysis of dark state rhodopsin, its photoactivated Meta II state and opsin suggested that the allosteric sites emerge only after light-induced rearrangement of TM helices within the Meta II and opsin structures and involve either rhodopsin's ICLs or ECLs.…”

Tauroursodeoxycholic acid binds to the G-protein site on light activated rhodopsin

“…Future biochemical and in-vivo studies will determine whether TUDCA’s ability to allosterically regulate rhodopsin can be utilized to modulate signaling properties of retinal photoreceptors. It is of particular interest in this context that a small molecule quercetin was demonstrated to act as an allosteric modulator of mutated forms of rhodopsin, such as RP-associated G90V, validating the concept of this new methodology (Herrera-Hernández et al, 2017). …”