Dynamical Correlations Reveal Allosteric Sites in G Protein-Coupled Receptors

Abstract

G protein-coupled Receptors (GPCRs) play a central role in many physiological processes and, consequently, constitute important drug targets. In particular, the search for allosteric drugs has recently drawn attention, since they could be more selective and lead to fewer side effects. Accordingly, computational tools have been used to estimate the druggability of allosteric sites in these receptors. In spite of many successful results, the problem is still challenging, particularly the prediction of hydrophobic sites in the interface between the protein and the membrane. In this work, we propose a complementary approach, based on dynamical correlations. Our basic hypothesis was that allosteric sites are strongly coupled to regions of the receptor that undergo important conformational changes upon activation. Therefore, using ensembles of experimental structures, normal mode analysis and molecular dynamics simulations we calculated correlations between internal fluctuations of different sites and a collective variable describing the activation state of the receptor. Then, we ranked the sites based on the strength of their coupling to the collective dynamics. In the β2 adrenergic (β2AR), glucagon (GCGR) and M2 muscarinic receptors, this procedure allowed us to correctly identify known allosteric sites, suggesting it has predictive value. Our results indicate that this dynamics-based approach can be a complementary tool to the existing toolbox to characterize allosteric sites in GPCRs.

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

“…Allosteric sites can be localized in all structural domains of the GPCRs ( Table 2 ). Estimation of the number and localization of allosteric sites in each receptor is a very difficult task, although significant progress in this direction has been made due to the development of new approaches for the identification of GPCR allosteric sites [ 61 , 62 , 84 , 85 ].…”

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

“…Unlike a single orthosteric site, the number of allosteric sites in GPCR can be very significant. Estimation of the number and localization of allosteric sites in each receptor is a very difficult task, although significant progress in this direction has been made due to the development of new approaches for the identification of GPCR allosteric sites [53,54,82,83].…”

“…Molecular dynamics methods can also be used to search for allosteric sites, and the most interesting here is the identification and study of allosteric sites located on the outerlateral surface of the TM7 bundle and, therefore, available for interaction with membrane lipids, as was recently shown for β2-AR, glucagon receptor, M2-muscarinic receptor, P2Y1 purinergic receptor, D2-dopamine receptor, type 2 proteinase-activated receptor (PAR2), C5a anaphylatoxin chemotactic 1 receptor [83,87,88]. Since these sites are involved in the formation and stabilization of receptor complexes (homo-and hetero-oligomeric), they mediate the allosteric effects of receptor di-and oligomerization on their functional activity.…”

Allosteric Modulators of G Protein-Coupled Receptors

“…In this Special Issue, Pedro Renault and Jesus Giraldo propose a new computational approach for the identification and study of allosteric sites in the GPCRs based on their assumption that such sites are strongly associated with those regions of the receptor that undergo the most significant conformational rearrangements upon its activation [ 3 ]. Using this approach, the allosteric sites have been identified in the β 2 -adrenergic and M 2 -muscarinic receptors (Type A GPCRs) and in the glucagon receptor (Type B GPCRs) and are shown to be in good agreement with data obtained using other methods.…”

“…Using this approach, the allosteric sites have been identified in the β 2 -adrenergic and M 2 -muscarinic receptors (Type A GPCRs) and in the glucagon receptor (Type B GPCRs) and are shown to be in good agreement with data obtained using other methods. Thus, despite some limitations, the proposed approach can become a useful tool for the search and characterization of allosteric sites in GPCRs, especially in cases where other approaches are not effective or suitable [ 3 ].…”