Getting Allosteric Control over Protein Activity: New Developments

Abstract

Allosteric regulation of protein activity via effector binding at distinct remote sites is under an unprecedented focus in current drug research. Potentially druggable allosteric sites are ubiquitous in most if not all dynamic proteins. The key advantages of targeting allosteric sites include the prospect of non-competitive remote fine-tuning of protein activity. As a result, the interest on simple quantitative models to uncover the mechanisms behind allosteric signaling is constantly increasing. We proposed a structure-based statistical mechanical model of allostery to quantify causality and energetics in allosteric signaling. The model considers binding as a perturbation of the protein dynamics and quantifies allosteric effects in terms of a per-residue free energy. The model was also extended to account for the allosteric effects induced by sequence mutations and it was recently included in a web server: “AlloSigMA”. AlloSigMA allows users to quantify the allosteric effect induced by binding and/or mutations. It also provides a rationale for the selection of allosterically relevant binding sites and mutations, which facilitate the design of experiments. Given the observation that perturbation of allosteric sites propagates signals to distal catalytic regions, we assumed the reversibility of allosteric signaling and hypothesized the detection of allosteric sites via perturbing the catalytic ones. The reverse signaling hypothesis was tested on a diverse set of 13 allosteric enzymes. We found that reverse signaling from catalytic sites allows the identification of the protein regions that most likely include allosteric sites. The predictive power of our method is positively correlated with the separation between allosteric and catalytic sites, consolidating the notion that allosteric regulation acts at distance. We conclude that reversible allosteric communication provide the foundation for the high-throughput screening of druggable allosteric sites via reverse signaling from the catalytic site.