The Structural Basis of ATP as an Allosteric Modulator

Abstract

Adenosine-5’-triphosphate (ATP) is generally regarded as a substrate for energy currency and protein modification. Recent findings uncovered the allosteric function of ATP in cellular signal transduction but little is understood about this critical behavior of ATP. Through extensive analysis of ATP in solution and proteins, we found that the free ATP can exist in the compact and extended conformations in solution, and the two different conformational characteristics may be responsible for ATP to exert distinct biological functions: ATP molecules adopt both compact and extended conformations in the allosteric binding sites but conserve extended conformations in the substrate binding sites. Nudged elastic band simulations unveiled the distinct dynamic processes of ATP binding to the corresponding allosteric and substrate binding sites of uridine monophosphate kinase, and suggested that in solution ATP preferentially binds to the substrate binding sites of proteins. When the ATP molecules occupy the allosteric binding sites, the allosteric trigger from ATP to fuel allosteric communication between allosteric and functional sites is stemmed mainly from the triphosphate part of ATP, with a small number from the adenine part of ATP. Taken together, our results provide overall understanding of ATP allosteric functions responsible for regulation in biological systems.

Regulation of the thermoalkaliphilic F 1 -ATPase from Caldalkalibacillus thermarum

“…S4). This conformation is characteristic of regulatory ATP molecules, whereas substrate ATP molecules are extended (35). The bound ATP is accompanied by a magnesium ion, and the O2A and O2B atoms of the ATP molecule provide two of the six ligands; the other four are almost certainly unresolved water molecules.…”

The Role of Conformational Dynamics and Allostery in the Disease Development of Human Ferritin

“…In PRS, we introduce perturbations by applying a random external unit force on single residues as a first-order approximation to the forces exerted on a protein in a crowded cell environment, then we analyze the residue response fluctuation profile of the rest of the chain using linear response theory. It has been shown that PRS using an elastic network model or coupled with MD can be useful to 1) obtain conformational changes upon binding (22,41); 2) identify critical residues that mediate long-range communication through dynamic allostery (10,65,(68)(69)(70); 3) predict a better binding affinity score through rapidly generating an ensemble of configurations for flexible docking (71)(72)(73); and 4) distinguish diseaseassociated and putatively neutral population variations in human proteome (27,28).…”

The Mechanism of ATP-Dependent Allosteric Protection of Akt Kinase Phosphorylation

“…Recent evidence indicates that ATP can also function as an allosteric modulator (Huang et al, 2014;Lu et al, 2014a). Thus, understanding the allosteric mechanism of ATP in Akt1 may provide broader insights into the role of ATP and its mechanism as an endogenous modulator in cell signaling and in an important class of enzymes (Nussinov and Tsai, 2013;Lu et al, 2014b).…”