Designing Molecular Spanners to Throw in the Protein Networks. Issue 21 (30th January 2020)

• Record Type: Journal Article
• Authors: Serapian, Stefano A.; Colombo, Giorgio
• Is Part Of: Chemistry. Volume 26:Issue 21(2020)
• Page Start: 4656
• Page End: 4670
• Publication Date: 2020-01-30
• Subjects: allostery -- drug design -- dynamics -- molecular recognition -- protein–protein interactions; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201904523
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: Proteins govern most aspects of cellular life and, through specific interfaces, are typically involved in intricate protein–protein interaction (PPI) networks and signaling pathways. Subtle up‐ or downregulation of key protein functions and PPIs results in disease; still, the preferred option to contrast the role of a protein in disease and healthy conditions alike remains its outright shutdown through orthosteric ligands that block its active site. Here, we explore subtler alternatives to modulate proteins and PPIs. Driven by a view of proteins as dynamic entities, we discuss ways to identify allosteric binding sites, which, when targeted by tailored ligands, can induce significant changes in the active site of a protein, and lead to agonistic or antagonistic effects. We also summarize the selective regulation of specific PPIs—either direct or allosteric—and show that effects can be stabilizing as well as destabilizing, depending on how the conformational equilibrium of a protein is shifted. Abstract : Out of the box : Shutting down protein function with orthosteric inhibitors is a drastic yet popular option. In this Minireview, we illustrate a range of alternatives, including allosteric approaches, to modulate protein functions and protein–protein interactions in a less indiscriminate manner.