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Modulation of enzyme structure and flexibility by substrate/ligand binding provides an important source of enzyme function regulation. Unfortunately, our understanding of the fundamental mechanisms coupling protein dynamics to biological function is still largely incomplete, therefore limiting our ability to harness protein conformational dynamics in order to regulate enzymatic activity. Here we couple variable temperature (VT) NMR, particularly relaxation dispersion experiments, X-ray crystallography, computer simulations, protein engineering, and enzyme kinetic assays to explore the role of structural heterogeneity and conformational disorder in regulation of the C-terminal substrate binding domain (EIC) of bacterial Enzyme I (EI). In particular, we investigate the relationship between structure, conformational dynamics, and biological function of four EIC constructs: the wild type mesophilic enzyme (eEIC), a thermophilic homologue (tEIC), and two hybrid constructs engineered by incorporating the active site loops of the mesophilic enzyme into the scaffold of the thermophilic enzyme (etEIC), and vice versa (teEIC). Through this characterization we provide evidence that the four EIC constructs are structurally similar and that holo EIC undergoes an exchange between a disordered expanded inactive state and a more ordered compact active state. Furthermore, we report that the population of the active state dictates the effective turnover number and that this functional regulation is achieved by tuning the thermodynamic balance between the active and inactive states providing rational for thermal adaption (i.e. why thermophilic homologues exhibit lower activity than their mesophilic counterpart at low temperatures but increased activity comparable to its mesophilic homologue at higher temperatures). We demonstrate that altering thermal stability, conformational flexibility,

Characterization of the C-terminal binding domain from bacterial Enzyme I