Allosteric communication regulates ligand‐specific GPCR activity

Abstract

Accepted Article This article is protected by copyright. All rights reserved G protein coupled receptors (GPCRs) are membrane bound proteins that are ubiquitously expressed in many cell types and take part in mediating multiple signaling pathways. GPCRs are dynamic proteins and exist in an equilibrium between an ensemble of conformational states such as inactive and fully active states. This dynamic nature of GPCRs is one of the factors that confers their basal activity even in the absence of any ligand mediated activation. Ligands selectively bind and stabilize a subset of the conformations from the ensemble leading to a shift in the equilibrium towards the inactive or the active state depending on the nature of the ligand. This ligand-selective effect is achieved through allosteric communication between the ligand binding site and G protein or -arrestin coupling site. Similarly, the G protein coupling to the receptor exerts the allosteric effect on the ligand binding region leading to increased binding affinity for agonists and decreased affinity for antagonists or inverse agonists. In this review, we enumerate the current state of our understanding of the mechanism of allosteric communication in GPCRs with a specific focus on the critical role of computational methods in delineating the residues involved in allosteric communication. Analyzing allosteric communication mechanism using molecular dynamics simulations have revealed (i) a structurally conserved mechanism of allosteric communication that regulates the G protein coupling, (ii) a rational structure-based approach to designing selective ligands and (iii) an approach to designing allosteric GPCR mutants that are either ligand and G protein or -arrestin selective.

In Silico Study of Allosteric Communication Networks in GPCR Signaling Bias

“…Such allosteric networks are highly complex and often comprise thousands of intramolecular contacts. Small molecules (e.g., full or partial agonists) are able to differentially engage those networks, which promote different intracellular coupling and signaling profiles [ 7 ]. Unfortunately, the structural fundamentals and associated correlated movements of biased signaling are still poorly understood, as experimental approaches provide only partial insights.…”

Conservation of Allosteric Ligand Binding Sites in G-Protein Coupled Receptors

“…Allosteric modulation of G protein-coupled receptors represents an alternative mechanism of pharmacological intervention and has been extensively studied. − By definition, allosteric modulators (AMs) bind to binding pockets different from the orthosteric site; however, they can impact the functional activity of the receptor in the presence of the endogenous ligand. Positive allosteric modulators (PAMs) potentiate, while negative allosteric modulators (NAMs) suppress the functional response of the receptor to the endogenous ligand.…”

Mechanistic basis of GPCR activation explored by ensemble refinement of crystallographic structures

“…Thus, accurate measurements of dynamic properties of GPCRs are essential in complementing structural information. Experimental techniques such as nuclear magnetic resonance (NMR) spectroscopy can be used to determine ensembles of conformational states, 27 , 28 , 36 , 37 , 38 , 39 , 40 , 41 , 42 and hydrogen‐deuterium exchange‐mass spectroscopy ( HDX‐MS) has been used to determine changes in the relative solvent accessibility of amide protons to reveal specific alterations in the energy landscapes of the receptors conformational states. 29 , 43 , 44 , 45 …”

“…Thus, accurate measurements of dynamic properties of GPCRs are essential in complementing structural information. Experimental techniques such as nuclear magnetic resonance (NMR) spectroscopy can be used to determine ensembles of conformational states, 27,28,[36][37][38][39][40][41][42] and hydrogendeuterium exchange-mass spectroscopy (HDX-MS) has been used to determine changes in the relative solvent accessibility of amide protons to reveal specific alterations in the energy landscapes of the receptors conformational states. 29,[43][44][45] An informative way to model the flexibility present in a crystallized protein is to represent the structure as a set of overlapping, noninteracting conformers each accounting for a fraction of the total electron density.…”