G protein-coupled receptors (GPCR) play important roles in human biology and are responsible for initiating the activation of several signaling pathways. These receptors follow a highly conserved mechanism of activation, in which an extracellular signal induces conformational changes in the receptor resulting in G protein activation. The activated G proteins are then capable of interacting with downstream effector enzymes that are responsible for mediating their physiological functions. Here in my thesis, I will first present a novel mechanism for the activation of the effector enzyme the cyclic GMP phosphodiesterase 6 (PDE6) by the G protein transducin, which represents a critical step in the signaling pathway responsible for vision in dim light. Phototransduction in retinal rods occurs when the G protein-coupled photoreceptor rhodopsin triggers the activation of phosphodiesterase 6 (PDE6) by GTP-bound alpha subunits of the G protein transducin (GαT). Here we demonstrate that 2:1 GαT-PDE6 complexes form with either recombinant or retinal GαT. We show that GαT binding is not necessary for the substrate cGMP nor competitive inhibitors to access the active sites; instead, occupancy of the substrate binding sites enables GαT to bind and reposition the PDE6γ subunits to promote catalytic activity. Moreover, we demonstrate by reconstituting GαT-stimulated PDE6 activity in lipid bilayer nanodiscs that the membrane-induced enhancement results from an increase in the apparent binding affinity of GαT for PDE6. These findings provide new insights into how the retinal G protein stimulates rapid catalytic turnover by PDE6 required for the remarkable signal amplification required for dim light vision. Secondly, I discuss the mechanism of activation and inhibition of transglutaminase 2 (TG2). TG2 is a multi-functional GTP-binding/protein-crosslinking enzyme that has been shown to be highly expressed in aggressive and malignant forms of cancer, while its expression is low in most normal cell types. TG2 has been suggested to adopt two conformational states that regulate its functions: a GTP-bound, closed conformation, and a calcium-bound, crosslinking-active open conformation. Biochemical studies of TG2 mutants that adopt an open conformation suggest this state is cytotoxic to cancer cells. Thus, small molecules that maintain the open conformation of TG2 in cancer cells could provide a novel therapeutic strategy. Here, we investigate TG2 using small-angle X-ray scattering (SAXS) and cryo-electron microscopy to determine the conformational changes responsible for conferring its biological effects. We also describe a new TG2 inhibitor, LM11, that is more potent than its predecessor and use SAXS to investigate how LM11 influences the conformation of TG2. We show that nucleotide-bound TG2 adopts a monomeric closed state conformation, while calcium-bound TG2 assumes an open conformational state that can oligomerize. Our analysis also shows how a TG2 mutant that adopts the open state binds guanine nucleotides using an alternative mechanism to wildtype TG2. Furthermore, we show that LM11 increases the ability of calcium to drive TG2 to an open conformation, which is irreversible by guanine nucleotides. Taken together, our findings demonstrate that the conformational dynamics of TG2 are more complex than previously suggested and highlight how conformational stabilization of TG2 by LM11 induces cytotoxicity in cancer cells and may open the way to new therapeutic strategies.