scholarly journals Allostery of atypical modulators at oligomeric G protein-coupled receptors

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rabindra V. Shivnaraine ◽  
Brendan Kelly ◽  
Gwendolynne Elmslie ◽  
Xi-Ping Huang ◽  
Yue John Dong ◽  
...  
Keyword(s):  
G Protein ◽  
Conformational Changes ◽  
Radioligand Binding ◽  
G Protein Coupled Receptors ◽  
Oligomeric State ◽  
Allosteric Sites ◽  
Functional Consequences ◽  
Orthosteric Ligands ◽  
Dynamics Simulations ◽  
G Protein Coupled

AbstractMany G protein-coupled receptors (GPCRs) are therapeutic targets, with most drugs acting at the orthosteric site. Some GPCRs also possess allosteric sites, which have become a focus of drug discovery. In the M2 muscarinic receptor, allosteric modulators regulate the binding and functional effects of orthosteric ligands through a mix of conformational changes, steric hindrance and electrostatic repulsion transmitted within and between the constituent protomers of an oligomer. Tacrine has been called an atypical modulator because it exhibits positive cooperativity, as revealed by Hill coefficients greater than 1 in its negative allosteric effect on binding and response. Radioligand binding and molecular dynamics simulations were used to probe the mechanism of that modulation in monomers and oligomers of wild-type and mutant M2 receptors. Tacrine is not atypical at monomers, which indicates that its atypical effects are a property of the receptor in its oligomeric state. These results illustrate that oligomerization of the M2 receptor has functional consequences.

scholarly journals Dynamical Correlations Reveal Allosteric Sites in G Protein-Coupled Receptors

2020 ◽  
Vol 22 (1) ◽  
pp. 187
Author(s):  
Pedro Renault ◽  
Jesús Giraldo
Keyword(s):  
G Protein ◽  
Conformational Changes ◽  
Drug Targets ◽  
Normal Mode Analysis ◽  
G Protein Coupled Receptors ◽  
Mode Analysis ◽  
Allosteric Sites ◽  
Basic Hypothesis ◽  
Dynamics Simulations ◽  
G Protein Coupled

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.

scholarly journals G Protein-Coupled Receptors Self-Assemble in Dynamics Simulations of Model Bilayers

2007 ◽  
Vol 129 (33) ◽  
pp. 10126-10132 ◽  
Author(s):  
Xavier Periole ◽  
Thomas Huber ◽  
Siewert-Jan Marrink ◽  
Thomas P. Sakmar
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Dynamics Simulations ◽  
G Protein Coupled

scholarly journals Trimethylsilyl reporter groups for NMR studies of conformational changes in G protein‐coupled receptors

FEBS Letters ◽  
2019 ◽  
Vol 593 (10) ◽  
pp. 1113-1121 ◽  
Author(s):  
Wanhui Hu ◽  
Huixia Wang ◽  
Yaguang Hou ◽  
Yimei Hao ◽  
Dongsheng Liu
Keyword(s):  
G Protein ◽  
Conformational Changes ◽  
G Protein Coupled Receptors ◽  
Nmr Studies ◽  
G Protein Coupled

scholarly journals Dissecting the allosteric networks governing agonist efficacy and potency in G protein-coupled receptors

2021 ◽  
Author(s):  
Franziska Marie Heydenreich ◽  
Maria Marti-Solano ◽  
Manbir Sandhu ◽  
Brian K Kobilka ◽  
Michel Bouvier ◽  
...  
Keyword(s):  
G Protein ◽  
Conformational Changes ◽  
Structural Changes ◽  
Receptor Activation ◽  
Residue Level ◽  
G Protein Coupled Receptors ◽  
Maximal Response ◽  
Pharmacological Properties ◽  
Receptor Ligand ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) translate binding of extracellular ligands into intracellular responses through conformational changes. Ligand properties are described by the maximum response (efficacy) and the agonist concentration at half-maximal response (potency). Integrating structural changes with pharmacological properties remains challenging and has not yet been performed at the resolution of individual amino acids. We use epinephrine and β2-adrenergic receptor as a model to integrate residue-level pharmacology data with intramolecular residue contact data describing receptor activation. This unveils the allosteric networks driving ligand efficacy and potency. We provide detailed insights into how structural rearrangements are linked to fundamental pharmacological properties at single-residue level in a receptor-ligand system. Our approach can be used to determine such pharmacological networks for any receptor-ligand complex.

scholarly journals Multiple GPCR Functional Assays Based on Resonance Energy Transfer Sensors

2021 ◽  
Vol 9 ◽  
Author(s):  
Yiwei Zhou ◽  
Jiyong Meng ◽  
Chanjuan Xu ◽  
Jianfeng Liu
Keyword(s):  
Energy Transfer ◽  
G Protein ◽  
Conformational Changes ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
G Protein Coupled Receptors ◽  
Functional Assays ◽  
High Throughput Drug Screening ◽  
Gpcr Activation ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) represent one of the largest membrane protein families that participate in various physiological and pathological activities. Accumulating structural evidences have revealed how GPCR activation induces conformational changes to accommodate the downstream G protein or β-arrestin. Multiple GPCR functional assays have been developed based on Förster resonance energy transfer (FRET) and bioluminescence resonance energy transfer (BRET) sensors to monitor the conformational changes in GPCRs, GPCR/G proteins, or GPCR/β-arrestin, especially over the past two decades. Here, we will summarize how these sensors have been optimized to increase the sensitivity and compatibility for application in different GPCR classes using various labeling strategies, meanwhile provide multiple solutions in functional assays for high-throughput drug screening.

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