Abstract
Nitric oxide (NO) plays an essential role in redox signaling in normal and pathological cellular conditions. In particular, it is well known to react in vivo with cysteines by the so-called S-nitrosylation reaction. S-nitrosylation is a selective and reversible post-translational modification that exerts a myriad of different effects, such as the modulation of protein conformation, activity, stability, and biological interaction networks. We have appreciated, over the last years, the role of S-nitrosylation in normal and disease conditions. In this context, structural and computational studies can help to dissect the complex and multifaceted role of this redox post-translational modification. In this review article, we summarized the current state-of-the-art on the mechanism of S-nitrosylation, along with the structural and computational studies that have helped to unveil its effects and biological roles. We also discussed the need to move new steps forward especially in the direction of employing computational structural biology to address the molecular and atomistic details of S-nitrosylation. Indeed, this redox modification has been so far an underappreciated redox post-translational modification by the computational biochemistry community. In our review, we primarily focus on S-nitrosylated proteins that are attractive cancer targets due to the emerging relevance of this redox modification in a cancer setting.
Highlights
Despite being amino acids (Cys) play diverse roles in biology
The discovery of S-nitrosylation opened new venues in the context of the cellular signaling induced by post-translational modifications since nitric oxide (NO) relies on this modification to transmit its redox signaling
As a result of extensive efforts by cellular and proteomics studies, we know several enzymatic regulators of S-nitrosylation, as well as a myriad of protein targets that are modulated by this post-translational modification
Summary
Despite being amino acids (Cys) play diverse roles in biology. they represent a special class of residues due to the thiol moiety of their side chain (Figure 1). It has been demonstrated that HRas undergoes S-nitrosylation on Cys118 with the effect of stabilizing the GTP-bound HRas form by enhancing the dissociation of guanine nucleotides [61] For this reason, it has been proposed that this PTM could represent a way to diversify the Ras-dependent oncogenic signaling beyond that of the mutated Ras. In summary, many examples have been provided of regulation of enzymatic activity by S-nitrosylation, and they are especially important in the context of kinases, G-coupled proteins and chaperones i.e., three usual suspects in a cancer setting. Many methods to study distal conformational changes, including methods based on MDderived ensemble, have been proposed and successfully applied to the study of long-range effects induced by protein PTMs such as phosphorylation or other perturbation of the protein native structure [32,33,34,35, 166,167,168] and they can be naturally translated to the study of allosteric effects promoted by S-nitrosylation
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