scholarly journals Allosteric Modulation of GPCRs of Class A by Cholesterol

2021 ◽  
Vol 22 (4) ◽  
pp. 1953
Author(s):  
Jan Jakubík ◽  
Esam E. El-Fakahany
Keyword(s):  
Binding Sites ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptors ◽  
Membrane Cholesterol ◽  
Extracellular Signals ◽  
High Affinity ◽  
Class A ◽  
Specific Effects ◽  
Induced Changes ◽  
G Protein Coupled

G-protein coupled receptors (GPCRs) are membrane proteins that convey extracellular signals to the cellular milieu. They represent a target for more than 30% of currently marketed drugs. Here we review the effects of membrane cholesterol on the function of GPCRs of Class A. We review both the specific effects of cholesterol mediated via its direct high-affinity binding to the receptor and non-specific effects mediated by cholesterol-induced changes in the properties of the membrane. Cholesterol binds to many GPCRs at both canonical and non-canonical binding sites. It allosterically affects ligand binding to and activation of GPCRs. Additionally, it changes the oligomerization state of GPCRs. In this review, we consider a perspective of the potential for the development of new therapies that are targeted at manipulating the level of membrane cholesterol or modulating cholesterol binding sites on to GPCRs.

scholarly journals Allosteric Modulation of GPCRs of Class A by Cholesterol

2021 ◽  
Author(s):  
Jan Jakubík ◽  
Esam E. El-Fakahany
Keyword(s):  
Binding Sites ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptors ◽  
Membrane Cholesterol ◽  
Extracellular Signals ◽  
High Affinity ◽  
Class A ◽  
Specific Effects ◽  
Induced Changes ◽  
G Protein Coupled

G-protein coupled receptors (GPCRs) are membrane proteins that convey extracellular signals to the cellular milieu. They represent a target for more than 30 % of currently marketed drugs. Here we review the effects of membrane cholesterol on the function of GPCRs of Class A. We review both the specific effects of cholesterol mediated via its direct high-affinity binding to the receptor and non-specific effects mediated by cholesterol-induced changes in the properties of the membrane. Cholesterol binds to many GPCRs at both canonical and non-canonical binding sites. It allosterically affects ligand binding to and activation of GPCRs. Also, it changes the oligomerization state of GPCRs. In this review, we consider a perspective of the potential for the development of new therapies that are targeted at manipulating the level of membrane cholesterol or modulating cholesterol binding sites on to GPCRs.

scholarly journals Unique Features of Different Classes of G-Protein-Coupled Receptors Revealed from Sequence Coevolutionary and Structural Analysis

2021 ◽  
Author(s):  
Hung Do ◽  
Allan Haldane ◽  
Ronald Levy ◽  
Yinglong Miao
Keyword(s):  
Structural Analysis ◽  
G Protein ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptors ◽  
Class A ◽  
Gpcr Activation ◽  
Residue Contacts ◽  
Critical Residue ◽  
Contact Frequency ◽  
G Protein Coupled

G-protein-coupled receptors (GPCRs) are the largest family of human membrane proteins and serve as the primary targets of about one third of currently marketed drugs. Despite the critical importance, experimental structures have been determined for only a limited portion of GPCRs. Functional mechanisms of GPCRs remain poorly understood. Here, we have constructed sequence coevolutionary models of the A, B and C classes of GPCRs and compared them with residue contact frequency maps generated with available experimental structures. Significant portions of structural residue contacts have been successfully detected in the sequence-based covariational models. "Exception" residue contacts predicted from sequence coevolutionary models but not available structures added missing links that were important for GPCR activation and allosteric modulation. Our combined coevolutionary and structural analysis revealed unique features of the different classes of GPCRs. First, we provided evidence from coevolutionary couplings that dimerization is required for activation of class C GPCRs, but not for activation of class A and B GPCRs. Second, we identified distinct residue contacts involving different sets of functional motifs for activation of the class A and B GPCRs. Finally, we uncovered critical residue contacts tuned by allosteric modulation in the three classes of GPCRs. These findings provide a promising framework for designing selective therapeutics of GPCRs.

scholarly journals Unique Features of Different Classes of G-Protein-Coupled Receptors Revealed from Sequence Coevolutionary and Structural Analysis

2021 ◽  
Author(s):  
Hung Do ◽  
Allan Haldane ◽  
Ronald M. Levy ◽  
Yinglong Miao
Keyword(s):  
G Protein ◽  
Rational Design ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptors ◽  
Class A ◽  
Gpcr Activation ◽  
Residue Contacts ◽  
Critical Residue ◽  
Contact Frequency ◽  
G Protein Coupled

G-protein-coupled receptors (GPCRs) are the largest family of human membrane proteins and represent the primary targets of about one third of currently marketed drugs. Despite the critical importance, experimental structures have been determined for only a limited portion of GPCRs and functional mechanisms of GPCRs remain poorly understood. Here, we have constructed novel sequence coevolutionary models of the A and B classes of GPCRs and compared them with residue contact frequency maps generated with available experimental structures. Significant portions of structural residue contacts were successfully detected in the sequence-based covariational models. “Exception” residue contacts predicted from sequence coevolutionary models but not available structures added missing links that were important for GPCR activation and allosteric modulation. Moreover, we identified distinct residue contacts involving different sets of functional motifs for GPCR activation, such as the Na+ pocket, CWxP, DRY, PIF and NPxxY motifs in the class A and the HETx and PxxG motifs in the class B. Finally, we systematically uncovered critical residue contacts tuned by allosteric modulation in the two classes of GPCRs, including those from the activation motifs and particularly the extracellular and intracellular loops in class A GPCRs. These findings provide a promising framework for rational design of ligands to regulate GPCR activation and allosteric modulation.

Spatiotemporal control of cAMP signalling processes by anchored signalling complexes

2007 ◽  
Vol 35 (5) ◽  
pp. 931-937 ◽  
Author(s):  
E. Jarnæss ◽  
K. Taskén
Keyword(s):  
Biological Effects ◽  
G Protein Coupled Receptors ◽  
Scaffolding Proteins ◽  
Extracellular Signals ◽  
Temporal Specificity ◽  
Anchoring Proteins ◽  
Induced Changes ◽  
Pka Pathway ◽  
Spatiotemporal Control ◽  
G Protein Coupled

Ligand-induced changes in cAMP concentration vary in duration, amplitude and extension into the cell. cAMP microdomains are shaped by adenylate cyclases that form cAMP as well as PDEs (phosphodiesterases) that degrade cAMP. Various extracellular signals converge on the cAMP/PKA (protein kinase A) pathway through ligand binding to GPCRs (G-protein-coupled receptors) and the cAMP/PKA pathway is therefore tightly regulated on several levels to maintain specificity in the multitude of signal inputs. AKAPs (A-kinase-anchoring proteins) target PKA to specific substrates and distinct subcellular compartments, providing spatial and temporal specificity for mediation of biological effects channelled through the cAMP/PKA pathway. AKAPs also serve as scaffolding proteins that assemble PKA together with signal terminators such as phosphoprotein phosphatases and cAMP-specific PDEs as well as components of other signalling pathways into multiprotein signalling complexes.

Multiple high-affinity binding sites for

1996 ◽  
Vol 199 (11) ◽  
pp. 2429-2435 ◽  
Author(s):  
S Winberg ◽  
G Nilsson
Keyword(s):  
Binding Sites ◽  
Arctic Charr ◽  
G Protein Coupled Receptors ◽  
Receptor Ligands ◽  
Site Model ◽  
High Affinity ◽  
Saturation Binding ◽  
High Affinity Site ◽  
G Protein Coupled ◽  
Binding Curve

Binding of [3H]serotonin (5-HT) to membranes prepared from Arctic charr brain homogenates was most consistent with a one-site model for [3H]5-HT binding, with KD and Bmax values of 5.7±0.3 nmol l-1 and 60.7±7.3 fmol mg-1 protein, respectively. Similarly, 5-HT displacement of [3H]5-HT was best explained by a monophasic model with an apparent Ki of 4.3±0.7 nmol l-1. The ability of a number of synthetic 5-HT receptor ligands to displace [3H]5-HT was studied. 8OH-DPAT was found to interact with three [3H]5-HT binding sites, whereas buspirone, TFMPP, spiperone and mianserin all distinguish two sites. In the presence of 300 nmol l-1 buspirone, 8OH-DPAT and mianserin distinguished two [3H]5-HT binding sites, whereas spiperone interacted with only one. Moreover, 8OH-DPAT differentiated three [3H]5-HT binding sites even in the presence of 0.5 mmol l-1 GTP, making it unlikely that these sites represent different affinity states of G-protein-coupled receptors. GTP had no effect on apparent Ki values for 8OH-DPAT, but reduced the Bmax value of the high-affinity site by 60 %. GTP had a similar effect on the saturation binding curve for [3H]5-HT, reducing Bmax by approximately 50 %, whereas KD was unaffected. The results provide evidence for at least three different high-affinity [3H]5-HT binding sites, one of them showing a pharmacological profile strikingly similar to that of the mammalian 5-HT1A receptor.

scholarly journals Locating ligand binding sites in G-protein coupled receptors using combined information from docking and sequence conservation

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e12219
Author(s):  
Ashley Ryan Vidad ◽  
Stephen Macaspac ◽  
Ho Leung Ng
Keyword(s):  
Ligand Binding ◽  
G Protein ◽  
Binding Sites ◽  
G Protein Coupled Receptors ◽  
Sequence Conservation ◽  
A2a Adenosine Receptors ◽  
Class A ◽  
Ligand Binding Sites ◽  
G Protein Coupled ◽  
Homology Models

GPCRs (G-protein coupled receptors) are the largest family of drug targets and share a conserved structure. Binding sites are unknown for many important GPCR ligands due to the difficulties of GPCR recombinant expression, biochemistry, and crystallography. We describe our approach, ConDockSite, for predicting ligand binding sites in class A GPCRs using combined information from surface conservation and docking, starting from crystal structures or homology models. We demonstrate the effectiveness of ConDockSite on crystallized class A GPCRs such as the beta2 adrenergic and A2A adenosine receptors. We also demonstrate that ConDockSite successfully predicts ligand binding sites from high-quality homology models. Finally, we apply ConDockSite to predict the ligand binding sites on a structurally uncharacterized GPCR, GPER, the G-protein coupled estrogen receptor. Most of the sites predicted by ConDockSite match those found in other independent modeling studies. ConDockSite predicts that four ligands bind to a common location on GPER at a site deep in the receptor cleft. Incorporating sequence conservation information in ConDockSite overcomes errors introduced from physics-based scoring functions and homology modeling.

scholarly journals Constitutive Activity among Orphan Class-A G Protein Coupled Receptors

PLoS ONE ◽  
2015 ◽  
Vol 10 (9) ◽  
pp. e0138463 ◽  
Author(s):  
Adam L. Martin ◽  
Michael A. Steurer ◽  
Robert S. Aronstam
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Constitutive Activity ◽  
Class A ◽  
G Protein Coupled

Steroids as the novel class of high-affinity allosteric modulators of muscarinic receptors

2021 ◽  
Author(s):  
Eva Dolejší ◽  
Eszter Szánti-Pintér ◽  
Nikolai Chetverikov ◽  
Dominik Nelic ◽  
Alena Randáková ◽  
...  
Keyword(s):  
Muscarinic Receptors ◽  
Acetylcholine Receptors ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptors ◽  
Muscarinic Acetylcholine Receptors ◽  
Allosteric Modulators ◽  
The Novel ◽  
Stress Control ◽  
Structure Activity ◽  
G Protein Coupled

Abstract The membrane cholesterol was found to bind and modulate the function of several G-protein coupled receptors including muscarinic acetylcholine receptors. We investigated the binding of 20 steroidal compounds including neurosteroids and steroid hormones to muscarinic receptors. Corticosterone, progesterone, and some neurosteroids bound to muscarinic receptors with an affinity of 100 nM or greater. We established a structure-activity relationship for steroid-based allosteric modulators of muscarinic receptors. Further, we show that corticosterone and progesterone allosterically modulate the functional response of muscarinic receptors to acetylcholine at physiologically relevant concentrations. It can play a role in stress control or in pregnancy, conditions where levels of these hormones dramatically oscillate. Allosteric modulation of muscarinic receptors via the cholesterol-binding site represents a new pharmacological approach at diseases associated with altered cholinergic signalling.

GPCR activation mechanisms across classes and macro/microscales

2021 ◽  
Author(s):  
David Gloriam ◽  
Alexander Hauser ◽  
Albert Kooistra ◽  
Christian Munk ◽  
M. Madan Babu
Keyword(s):  
Residue Level ◽  
G Protein Coupled Receptors ◽  
Conformational Selection ◽  
Class A ◽  
New Methods ◽  
Allosteric Communication ◽  
Gpcr Activation ◽  
Activation Mechanisms ◽  
Clinical Drugs ◽  
G Protein Coupled

Abstract Two-thirds of human hormones and one-third of clinical drugs activate ~350 G protein-coupled receptors belonging to four classes: A, B1, C and F. Whereas a model of activation has been described for class A, very little is known about the activation of the other classes which differ by being activated by endogenous ligands bound mainly or entirely extracellularly. Here, we show that although they use the same structural scaffold and share several helix macroswitches, the GPCR classes differ in their microswitch residue positions and contacts. We present molecular mechanistic maps of activation for each GPCR class and new methods for contact analysis applicable for any functional determinants. This is the first superfamily residue-level rationale for conformational selection and allosteric communication by ligands and G proteins laying the foundation for receptor-function studies and drugs with the desired modality.

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