scholarly journals Allosteric modulation in monomers and oligomers of a G protein-coupled receptor

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Rabindra V Shivnaraine ◽  
Brendan Kelly ◽  
Krishana S Sankar ◽  
Dar'ya S Redka ◽  
Yi Rang Han ◽  
...  
Keyword(s):  
Muscarinic Receptor ◽  
Allosteric Modulation ◽  
Atomic Level ◽  
Allosteric Site ◽  
Allosteric Interactions ◽  
M2 Muscarinic Receptor ◽  
Orthosteric Ligands ◽  
Dynamics Simulations ◽  
G Protein Coupled ◽  
Allosteric Properties

The M2 muscarinic receptor is the prototypic model of allostery in GPCRs, yet the molecular and the supramolecular determinants of such effects are unknown. Monomers and oligomers of the M2 muscarinic receptor therefore have been compared to identify those allosteric properties that are gained in oligomers. Allosteric interactions were monitored by means of a FRET-based sensor of conformation at the allosteric site and in pharmacological assays involving mutants engineered to preclude intramolecular effects. Electrostatic, steric, and conformational determinants of allostery at the atomic level were examined in molecular dynamics simulations. Allosteric effects in monomers were exclusively negative and derived primarily from intramolecular electrostatic repulsion between the allosteric and orthosteric ligands. Allosteric effects in oligomers could be positive or negative, depending upon the allosteric-orthosteric pair, and they arose from interactions within and between the constituent protomers. The complex behavior of oligomers is characteristic of muscarinic receptors in myocardial preparations.

scholarly journals Interfacial Water Many-body Effects Drive Structural Dynamics and Allosteric interactions in SARS-CoV-2 Main Protease Dimerization Interface

2021 ◽  
Author(s):  
Dina El Ahdab ◽  
Louis Lagardère ◽  
Theo Jaffrelot Inizan ◽  
Frédéric Célerse ◽  
Chengwen Liu ◽  
...  
Keyword(s):  
Structural Dynamics ◽  
Adaptive Sampling ◽  
Many Body ◽  
Allosteric Site ◽  
Allosteric Interactions ◽  
Main Protease ◽  
Dimerization Interface ◽  
Bond Network ◽  
Dynamics Simulations ◽  
Many Body Interactions

Following our previous work (Chem. Sci., 2021, 12, 4889 – 4907), we study the structural dynamics of the SARS-CoV-2 Main Protease dimerization interface (apo dimer) by means of microsecond adaptive sampling molecular dynamics simulations (50 microseconds) using the AMOEBA polarizable force field (PFF). This interface is structured by a complex H-bond network that is only stable at physiological pH. Structural correlations analysis between its residues and the catalytic site confirms the presence of a buried allosteric site. However, noticeable differences in allosteric connectivity are observed between PFFs and non-PFFs. Interfacial polarizable water molecules are shown to appear at the heart of this discrepancy, since they are connected to the global interface H-bond network and able to adapt their dipole moment (and dynamics) to their diverse local physico-chemical micro-environments. The water-interface many-body interactions appear to drive the interface volume fluctuations and to therefore mediate the allosteric interactions with the catalytic cavity.

scholarly journals Repositioning Dequalinium as Potent Muscarinic Allosteric Ligand by Combining Virtual Screening Campaigns and Experimental Binding Assays

2020 ◽  
Vol 21 (17) ◽  
pp. 5961
Author(s):  
Angelica Mazzolari ◽  
Silvia Gervasoni ◽  
Alessandro Pedretti ◽  
Laura Fumagalli ◽  
Rosanna Matucci ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Allosteric Modulation ◽  
Allosteric Modulators ◽  
Binding Assays ◽  
Docking Protocol ◽  
Consensus Models ◽  
Binding Cavity ◽  
Orthosteric Ligands ◽  
G Protein Coupled

Structure-based virtual screening is a truly productive repurposing approach provided that reliable target structures are available. Recent progresses in the structural resolution of the G-Protein Coupled Receptors (GPCRs) render these targets amenable for structure-based repurposing studies. Hence, the present study describes structure-based virtual screening campaigns with a view to repurposing known drugs as potential allosteric (and/or orthosteric) ligands for the hM2 muscarinic subtype which was indeed resolved in complex with an allosteric modulator thus allowing a precise identification of this binding cavity. First, a docking protocol was developed and optimized based on binding space concept and enrichment factor optimization algorithm (EFO) consensus approach by using a purposely collected database including known allosteric modulators. The so-developed consensus models were then utilized to virtually screen the DrugBank database. Based on the computational results, six promising molecules were selected and experimentally tested and four of them revealed interesting affinity data; in particular, dequalinium showed a very impressive allosteric modulation for hM2. Based on these results, a second campaign was focused on bis-cationic derivatives and allowed the identification of other two relevant hM2 ligands. Overall, the study enhances the understanding of the factors governing the hM2 allosteric modulation emphasizing the key role of ligand flexibility as well as of arrangement and delocalization of the positively charged moieties.

scholarly journals Interfacial Water Many-body Effects Drive Structural Dynamics and Allosteric interactions in SARS-CoV-2 Main Protease Dimerization Interface

2021 ◽  
Author(s):  
Dina El Ahdab ◽  
Louis Lagardère ◽  
Theo Jaffrelot Inizan ◽  
Frédéric Célerse ◽  
Chengwen Liu ◽  
...  
Keyword(s):  
Structural Dynamics ◽  
Adaptive Sampling ◽  
Many Body ◽  
Allosteric Site ◽  
Allosteric Interactions ◽  
Main Protease ◽  
Dimerization Interface ◽  
Bond Network ◽  
Dynamics Simulations ◽  
Many Body Interactions

Following our previous work (Chem. Sci., 2021, 12, 4889 – 4907), we study the structural dynamics of the SARS-CoV-2 Main Protease dimerization interface (apo dimer) by means of microsecond adaptive sampling molecular dynamics simulations (50 microseconds) using the AMOEBA polarizable force field (PFF). This interface is structured by a complex H-bond network that is only stable at physiological pH. Structural correlations analysis between its residues and the catalytic site confirms the presence of a buried allosteric site. However, noticeable differences in allosteric connectivity are observed between PFFs and non-PFFs. Interfacial polarizable water molecules are shown to appear at the heart of this discrepancy, since they are connected to the global interface H-bond network and able to adapt their dipole moment (and dynamics) to their diverse local physico-chemical micro-environments. The water-interface many-body interactions appear to drive the interface volume fluctuations and to therefore mediate the allosteric interactions with the catalytic cavity.

scholarly journals Current Advances in Allosteric Modulation of Muscarinic Receptors

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 325 ◽  
Author(s):  
Jan Jakubik ◽  
Esam E. El-Fakahany
Keyword(s):  
Muscarinic Receptors ◽  
Acetylcholine Receptors ◽  
Allosteric Modulation ◽  
Muscarinic Acetylcholine Receptors ◽  
Allosteric Modulators ◽  
Pharmacological Agents ◽  
Orthosteric Ligands ◽  
A Site ◽  
G Protein Coupled

Allosteric modulators are ligands that bind to a site on the receptor that is spatially separated from the orthosteric binding site for the endogenous neurotransmitter. Allosteric modulators modulate the binding affinity, potency, and efficacy of orthosteric ligands. Muscarinic acetylcholine receptors are prototypical allosterically-modulated G-protein-coupled receptors. They are a potential therapeutic target for the treatment of psychiatric, neurologic, and internal diseases like schizophrenia, Alzheimer’s disease, Huntington disease, type 2 diabetes, or chronic pulmonary obstruction. Here, we reviewed the progress made during the last decade in our understanding of their mechanisms of binding, allosteric modulation, and in vivo actions in order to understand the translational impact of studying this important class of pharmacological agents. We overviewed newly developed allosteric modulators of muscarinic receptors as well as new spin-off ideas like bitopic ligands combining allosteric and orthosteric moieties and photo-switchable ligands based on bitopic agents.

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 Interfacial Water Many-body Effects Drive Structural Dynamics and Allosteric interactions in SARS-CoV-2 Main Protease Dimerization Interface

2021 ◽  
Author(s):  
Dina El Ahdab ◽  
Louis Lagardère ◽  
Theo Jaffrelot Inizan ◽  
Frédéric Célerse ◽  
Chengwen Liu ◽  
...  
Keyword(s):  
Structural Dynamics ◽  
Adaptive Sampling ◽  
Many Body ◽  
Allosteric Site ◽  
Allosteric Interactions ◽  
Main Protease ◽  
Dimerization Interface ◽  
Bond Network ◽  
Dynamics Simulations ◽  
Many Body Interactions

Following our previous work (Chem. Sci., 2021, 12, 4889 – 4907), we study the structural dynamics of the SARS-CoV-2 Main Protease dimerization interface (apo dimer) by means of microsecond adaptive sampling molecular dynamics simulations (50 microseconds) using the AMOEBA polarizable force field (PFF). This interface is structured by a complex H-bond network that is only stable at physiological pH. Structural correlations analysis between its residues and the catalytic site confirms the presence of a buried allosteric site. However, noticeable differences in allosteric connectivity are observed between PFFs and non-PFFs. Interfacial polarizable water molecules are shown to appear at the heart of this discrepancy, since they are connected to the global interface H-bond network and able to adapt their dipole moment (and dynamics) to their diverse local physico-chemical micro-environments. The water-interface many-body interactions appear to drive the interface volume fluctuations and to therefore mediate the allosteric interactions with the catalytic cavity.

The voltage-sensitive cardiac M2 muscarinic receptor modulates the inward rectification of the G protein-coupled, ACh-gated K+ current

2018 ◽  
Vol 470 (12) ◽  
pp. 1765-1776 ◽  
Author(s):  
Pedro D. Salazar-Fajardo ◽  
Iván A. Aréchiga-Figueroa ◽  
Ana Laura López-Serrano ◽  
Julio C. Rodriguez-Elias ◽  
Javier Alamilla ◽  
...  
Keyword(s):  
G Protein ◽  
Muscarinic Receptor ◽  
Inward Rectification ◽  
M2 Muscarinic Receptor ◽  
K Current ◽  
G Protein Coupled
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