Abstract
Structural and biochemical studies on diverse enzymes have highlighted the importance of ligand-gated conformational changes in enzyme catalysis, where the intrinsic binding energy of the common phosphoryl group of their substrates is used to drive energetically unfavorable conformational changes in catalytic loops, from inactive open to catalytically competent closed conformations. However, computational studies have historically been unable to capture the activating role of these conformational changes. Here, we discuss recent experimental and computational studies, which can remarkably pinpoint the role of ligand-gated conformational changes in enzyme catalysis, even when not modeling the loop dynamics explicitly. Finally, through our joint analyses of these data, we demonstrate how the synergy between theory and experiment is crucial for furthering our understanding of enzyme catalysis.
Highlights
Daniel Koshland proposed in 1958 that the specificity of aminoacyl t-RNA synthases for charging their cognate amino acids to t-RNA is obtained through the utilization of binding interactions between the synthase and the cognate α-amino acid side chain, to induce a change in protein structure that draws the enzyme catalytic groups into their active conformation [1]
We have examined the mechanism of action of three enzymes that undergo ligand-gated conformational changes: triosephosphate isomerase (TIM) [7,8], orotidine 50-monophosphate decarboxylase (OMPDC) [9], and glycerol 3-phosphate dehydrogenase (GPDH) [10,11]
We describe in this review the mechanistic rationale for the utilization of the binding energy of the phosphoryl group of the substrate to drive these ligandgated conformational changes, the common structural elements for the three enzyme conformational changes, as well as the results of ongoing computational studies to model the role of this conformational change in catalysis by TIM
Summary
Daniel Koshland proposed in 1958 that the specificity of aminoacyl t-RNA synthases for charging their cognate amino acids to t-RNA is obtained through the utilization of binding interactions between the synthase and the cognate α-amino acid side chain, to induce a change in protein structure that draws the enzyme catalytic groups into their active conformation [1]. The ligand-gated conformational changes undergone by TIM, OMPDC, and GPDH each conform to the Koshland’s induced fit model, where the binding energy of the dianion of the phosphoryl group (or phosphite dianion in the case of the binding of the substrate fragments) is utilized to induce an enzymatic conformational change, from the inactive open protein to the catalytically active closed form.
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