Fine-Tuning Multiprotein Complexes Using Small Molecules

Abstract

Multi-protein complexes such as the transcriptional machinery, signaling hubs, and protein folding machines are typically comprised of at least one enzyme combined with multiple non-enzymes. Often the components of these complexes are incorporated in a combinatorial manner, in which the ultimate composition of the system helps dictate the type, location, or duration of cellular activities. Although drugs and chemical probes have traditionally targeted the enzyme components, emerging strategies call for controlling the function of protein complexes by modulation of protein-protein interactions (PPI). However, the challenges of targeting PPIs have been well documented and the diversity of PPIs makes a “one-size-fits-all” solution highly unlikely. These hurdles are particularly daunting for PPIs that encompass large buried surface areas and those with weak affinities. In this review, we discuss lessons from natural systems, in which allostery and other mechanisms are used to overcome the challenge of regulating the most difficult PPIs. These systems may provide a blueprint for identifying small molecules that target challenging PPIs and affecting molecular decision-making within multi-protein systems.

In vivo modulation of hypoxia-inducible signaling by topographical helix mimetics

“…Despite their fundamental importance in biological signaling, relatively few small-molecule inhibitors have been discovered, underscoring the difficulty in inhibiting large interfaces (2). Recent analyses suggest that PPIs may be categorized as those that are amenable to inhibition by small molecules and those that will require large molecules (3)(4)(5). Key to these analyses is the recognition that although PPIs encompass larger surface areas than enzyme-substrate complexes, a handful of key residues dominate the binding energy landscape (6,7).…”

Dissecting allosteric effects of activator–coactivator complexes using a covalent small molecule ligand

“…IDP | protein-protein interaction P rotein-protein interactions (PPIs) underscore all cellular processes, and the mechanistic dissection of PPI networks is thus a high priority (1)(2)(3)(4). A particular challenge is defining the mechanism of PPI formation between intrinsically disordered proteins (IDPs) where allosteric changes play a substantive role (5)(6)(7).…”

Host–rabies virus protein–protein interactions as druggable antiviral targets

“…MPCs represent the core of the protein-protein interaction (PPI) networks responsible for a multitude of biological functions (23,24). Effective therapeutic modulation of MPC PPIs would be powerful (25,26), but a history of unsuccessful attempts has led to the widespread opinion that such targets are not druggable (19). We hypothesize that these setbacks can be attributed to the limitations imposed by both traditional drugs and traditional approaches to drug discovery and that a different approach might be successful.…”

“…First, most existing small-molecule drugs achieve their activity by competing directly with an endogenous molecule for a functional binding site (19). This type of mechanism is not easily applied to MPCs, which often involve large binding surfaces, weak affinities, transient interactions, and disordered protein regions (26,27). Biological systems generally modulate PPIs through allostery rather than direct inhibition, indicating that binding an allosteric site is much more likely to be an effective mechanism for drug action against MPC targets (26).…”

“…This type of mechanism is not easily applied to MPCs, which often involve large binding surfaces, weak affinities, transient interactions, and disordered protein regions (26,27). Biological systems generally modulate PPIs through allostery rather than direct inhibition, indicating that binding an allosteric site is much more likely to be an effective mechanism for drug action against MPC targets (26). Second, the predominant approach to drug discovery involves identifying a specific target before finding a lead compound, thereby limiting discovery to targets of sufficient stability for conventional purification.…”