Chemical and Biophysical Approaches to Allosteric Modulation

Abstract

Allosteric regulation, i. e. the control exerted on an orthosteric site by an effector interacting at a distinct and distant site, represents a prime example of a precise tuning system of several key biological processes like gene transcription, cell adhesion and, most importantly, signal transduction. Since its discovery sixty years ago, the molecular mechanisms underlying this phenomenon have been extensively investigated. The aim of this minireview is to introduce the reader to the topic of protein allostery. In particular, we briefly overview the allosteric models postulated over the years and we describe the most relevant chemical and biophysical approaches reported so far for the identification of putative allosteric sites and/or for the investigation of allosteric signal propagation throughout the protein. An outlook of the main computational and experimental methods is followed by four case studies representative of different proteins classes: enzymes, hub proteins, cell receptors, and intrinsically disordered proteins.

Glycomimetics for the inhibition and modulation of lectins

“…For carbohydrate-binding proteins, an approach targeting a druggable allosteric site is very attractive compared to focusing on the orthosteric, hydrophilic, flat and solvent-exposed carbohydrate binding site. 44,569,601 Finally, this opens the question for the biological relevance of such sites in lectins.…”

Allosteric crosstalk in modular proteins: Function fine-tuning and drug design

“…There are several ways to understand allosteric mechanisms, which can be further translated to either direct medical applications or green chemistry for the biosynthesis of compounds with agricultural or healthcare applications. Apart from the approaches discussed above, several computational and experimental approaches to studying allostery have been discussed in detail by the Sattin group [108] .…”