G-protein coupled receptors (GPCRs) are involved in many pathological processes and implicated in many diseases; over 50% of the drugs target GPCRs. Rhodopsin, the retinal GPCR, is used as the prototypical GPCR because it is the only GPCR for which an X-ray structure exists. Following light exposure, rhodopsin changes conformation (R->R*), allowing its G-protein, transducin, to bind. The interaction of the transducin C-terminal region Gtalpha(340-350) with the intracellular loops of rhodopsin is critical for GDP/GTP exchange and subsequent signal amplification in the vision cascade. Some congenital mutations in rhodopsin cause rhodopsin to stay in the R* state, leading to constitutive signal amplification. The goal of my research is to learn about the molecular recognition between rhodopsin and transducin and develop a molecular therapeutic to block this interaction. Using both experimental and computational techniques, I will determine the binding mode and residue-residue interactions of Gtalpha(340-350) peptides and peptidomimetics with R*. I will use parallel techniques to derive a small molecule to inhibit the rhodopsin/transducin interaction. First, I will use modeling software and computational high-throughput screening to design an inhibitor. Secondly, I will explore the use of high-efficiency reactions to generate peptidomimetic compounds using rhodopsin to template the reaction. Statement of Relevance: Despite a large number of drugs on the market targeting G-protein coupled receptors (GPCRs), very little is known about how GPCRs interact with other proteins and signal downstream processes. Using rhodopsin, the prototypical GPCR involved in vision, I will determine how rhodopsin and transducin (rhodopsin's G-protein) interact using experimental and computational methods, and I will design and test a small molecule to block this interaction. This work will provide general information about how GPCRs interact with G-proteins and potentially lead to a small molecule therapeutic for some congenital retinal diseases. ? ? ?
| Taylor, Christina M; Rockweiler, Nicole B; Liu, Cassie et al. (2010) Using ligand-based virtual screening to allosterically stabilize the activated state of a GPCR. Chem Biol Drug Des 75:325-32 |
| Nikiforovich, Gregory V; Taylor, Christina M; Marshall, Garland R et al. (2010) Modeling the possible conformations of the extracellular loops in G-protein-coupled receptors. Proteins 78:271-85 |
| Taylor, Christina M; Barda, Yaniv; Kisselev, Oleg G et al. (2008) Modulating G-protein coupled receptor/G-protein signal transduction by small molecules suggested by virtual screening. J Med Chem 51:5297-303 |
