In this context, there have been extensive studies of a wide-range of enzymes, such as triosephosphate isomerase (TPI), orotidine 5'-monophosphate decarboxylase, (OMPDC) glycerol 3-phosphate dehydrogenase (GPDH), 1-deoxy-D-xylulose-5-phosphate reductoisomerase, and β-phosphoglucomutase, which have been demonstrated to be activated by ligand-gated conformational changes. Specifically, interactions between a key "gripper" loop decorating the active site and the non-reactive phosphodianion groups of the substrates of these enzymes trigger substantial conformational changes in the gripper loop, facilitating energetically unfavorable transitions from catalytically inactive open to catalytically active closed conformations, and these conformational transitions are central to the catalytic activities and high proficiencies of these enzymes. It is noteworthy that several of the aforementioned enzymes have TIM-barrel folds. This fold comprises eight repeated (βα)-units, and most if not all TIM-barrel proteins possess decorating loops, the conformational diversity of which likely plays an important role in regulating specificity and function. These flexible loops can vary in length, but are typically used to bind substrate, and to sequester the active site from solvent by closing over the active site, and it has been suggested that the active site geometries of these enzymes are shaped by the residues of these loops. However, these well-characterized examples of proteins activated by ligand-gated conformational changes all focus on the roles and importance of single loops, such as gripper loop 6 in TPI. Studying the ligand-gated motion of a single loop can already pose substantial challenges; systems with multiple active site loops undergoing substantial conformational changes are even more complex, and therefore unsurprisingly understudied in the literature.