Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Intracellular Receptor Modulation: Novel Approach to Target GPCRs.

ABSTRACT: Recent crystal structures of multiple G protein-coupled receptors (GPCRs) have revealed a highly conserved intracellular pocket that can be used to modulate these receptors from the inside. This novel intracellular site partially overlaps with the G protein and ?-arrestin binding site, providing a new manner of pharmacological intervention. Here we provide an update of the architecture and function of the intracellular region of GPCRs, until now portrayed as the signaling domain. We review the available evidence on the presence of intracellular binding sites among chemokine receptors and other class A GPCRs, as well as different strategies to target it, including small molecules, pepducins, and nanobodies. Finally, the potential advantages of intracellular (allosteric) ligands over orthosteric ligands are also discussed.

SUBMITTER: Ortiz Zacarias NV

PROVIDER: S-EPMC7048003 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Intracellular Receptor Modulation: Novel Approach to Target GPCRs.

Ortiz Zacarías Natalia V NV Lenselink Eelke B EB IJzerman Adriaan P AP Handel Tracy M TM Heitman Laura H LH

Trends in pharmacological sciences 20180410 6

Recent crystal structures of multiple G protein-coupled receptors (GPCRs) have revealed a highly conserved intracellular pocket that can be used to modulate these receptors from the inside. This novel intracellular site partially overlaps with the G protein and β-arrestin binding site, providing a new manner of pharmacological intervention. Here we provide an update of the architecture and function of the intracellular region of GPCRs, until now portrayed as the signaling domain. We review the a ...[more]

PMID: 29653834

Similar Datasets

Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders.

Project description:Despite G-protein-coupled receptors (GPCRs) being among the most fruitful targets for marketed drugs, intense discovery efforts for several GPCR subtypes have failed to deliver selective drug candidates. Historically, drug discovery programmes for GPCR ligands have been dominated by efforts to develop agonists and antagonists that act at orthosteric sites for endogenous ligands. However, in recent years, there have been tremendous advances in the discovery of novel ligands for GPCRs that act at allosteric sites to regulate receptor function. These compounds provide high selectivity, novel modes of efficacy and may lead to novel therapeutic agents for the treatment of multiple psychiatric and neurological human disorders.

| S-EPMC2907734 | biostudies-literature

Modulation of the chemokine/chemokine receptor axis as a novel approach for glioma therapy.

Project description:Chemokines are a large subfamily of cytokines known for their ability to facilitate cell migration, most notably leukocytes, throughout the body. Chemokines are necessary for a functioning immune system in both health and disease and have received considerable attention for their roles in orchestrating temporal-spatial regulation of immune cell populations in cancer. Gliomas comprise a group of common central nervous system (CNS) primary tumors that are extremely challenging to treat. Immunotherapy approaches for highly malignant brain tumors offer an exciting new avenue for therapeutic intervention but so far, have seen limited successful clinical outcomes. Herein we focus on important chemokine/chemokine receptor systems in the regulation of pro- and anti-tumor mechanisms, highlighting potential therapeutic advantages of modulating these systems in malignant gliomas and other cancers.

| S-EPMC8122077 | biostudies-literature

Modulation of glycine receptor single-channel conductance by intracellular phosphorylation.

Project description:Glycine receptors (GlyRs) are anion-permeable pentameric ligand-gated ion channels (pLGICs). The GlyR activation is critical for the control of key neurophysiological functions, such as motor coordination, respiratory control, muscle tone and pain processing. The relevance of the GlyR function is further highlighted by the presence of abnormal glycinergic inhibition in many pathophysiological states, such as hyperekplexia, epilepsy, autism and chronic pain. In this context, previous studies have shown that the functional inhibition of GlyRs containing the ?3 subunit is a pivotal mechanism of pain hypersensitivity. This pathway involves the activation of EP2 receptors and the subsequent PKA-dependent phosphorylation of ?3GlyRs within the intracellular domain (ICD), which decrease the GlyR-associated currents and enhance neuronal excitability. Despite the importance of this mechanism of glycinergic dis-inhibition associated with dysfunctional ?3GlyRs, our current understanding of the molecular events involved is limited. Here, we report that the activation of PKA signaling pathway decreases the unitary conductance of ?3GlyRs. We show in addition that the substitution of the PKA-targeted serine with a negatively charged residue within the ICD of ?3GlyRs and of chimeric receptors combining bacterial GLIC and ?3GlyR was sufficient to generate receptors with reduced conductance. Thus, our findings reveal a potential biophysical mechanism of glycinergic dis-inhibition and suggest that post-translational modifications of the ICD, such as phosphorylation, may shape the conductance of other pLGICs.

| S-EPMC7076024 | biostudies-literature

Allosteric Modulation of GPCRs of Class A by Cholesterol.

Project description: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.

| S-EPMC7920425 | biostudies-literature

Covalent allosteric modulation: An emerging strategy for GPCRs drug discovery.

Project description:Designing covalent allosteric modulators brings new opportunities to the field of drug discovery towards G-protein-coupled receptors (GPCRs). Targeting an allosteric binding pocket can allow a modulator to have protein subtype selectivity and low drug resistance. Utilizing covalent warheads further enables the modulator to increase the binding potency and extend the duration of action. This review starts with GPCR allosteric modulation to discuss the structural biology of allosteric binding pockets, the different types of allosteric modulators, as well as the advantages of employing allosteric modulation. This is followed by a discussion on covalent modulators to clarify how covalent ligands can benefit the receptor modulation and to illustrate moieties that can commonly be used as covalent warheads. Finally, case studies are presented on designing class A, B, and C GPCR covalent allosteric modulators to demonstrate successful stories on combining allosteric modulation and covalent binding. Limitations and future perspectives are also covered.

| S-EPMC9948676 | biostudies-literature

Identification of novel bladder sensory GPCRs.

Project description:Sensory GPCRs such as olfactory receptors (ORs), taste receptors (TRs), and opsins (OPNs) are now known to play important physiological roles beyond their traditional sensory organs. Here, we systematically investigate the expression of sensory GPCRs in the urinary bladder for the first time. We find that the murine bladder expresses 16 ORs, 7 TRs, and 3 OPNs. We additionally explore the ectopic expression of these GPCRs in tissues beyond the bladder, as well as the localization within the bladder. In future work, understanding the functional roles of these bladder sensory GPCRs may shed light on novel mechanisms which modulate bladder function in health and disease.

| S-EPMC8087981 | biostudies-literature

Molecular mechanism of allosteric modulation at GPCRs: insight from a binding kinetics study at the human A1 adenosine receptor.

Project description:Background and purposeMany GPCRs can be allosterically modulated by small-molecule ligands. This modulation is best understood in terms of the kinetics of the ligand-receptor interaction. However, many current kinetic assays require at least the (radio)labelling of the orthosteric ligand, which is impractical for studying a range of ligands. Here, we describe the application of a so-called competition association assay at the adenosine A1 receptor for this purpose.Experimental approachWe used a competition association assay to examine the binding kinetics of several unlabelled orthosteric agonists of the A1 receptor in the absence or presence of two allosteric modulators. We also tested three bitopic ligands, in which an orthosteric and an allosteric pharmacophore were covalently linked with different spacer lengths. The relevance of the competition association assay for the binding kinetics of the bitopic ligands was also explored by analysing simulated data.Key resultsThe binding kinetics of an unlabelled orthosteric ligand were affected by the addition of an allosteric modulator and such effects were probe- and concentration-dependent. Covalently linking the orthosteric and allosteric pharmacophores into one bitopic molecule had a substantial effect on the overall on- or off-rate.Conclusion and implicationsThe competition association assay is a useful tool for exploring the allosteric modulation of the human adenosine A1 receptor. This assay may have general applicability to study allosteric modulation at other GPCRs as well.

| S-EPMC4294041 | biostudies-literature

A novel modulation classification approach using Gabor filter network.

Project description:A Gabor filter network based approach is used for feature extraction and classification of digital modulated signals by adaptively tuning the parameters of Gabor filter network. Modulation classification of digitally modulated signals is done under the influence of additive white Gaussian noise (AWGN). The modulations considered for the classification purpose are PSK 2 to 64, FSK 2 to 64, and QAM 4 to 64. The Gabor filter network uses the network structure of two layers; the first layer which is input layer constitutes the adaptive feature extraction part and the second layer constitutes the signal classification part. The Gabor atom parameters are tuned using Delta rule and updating of weights of Gabor filter using least mean square (LMS) algorithm. The simulation results show that proposed novel modulation classification algorithm has high classification accuracy at low signal to noise ratio (SNR) on AWGN channel.

| S-EPMC4122807 | biostudies-other

Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts.

Project description:G-protein-coupled receptors (GPCRs) have been tractable drug targets for decades with over one-third of currently marketed drugs targeting GPCRs. Of these, the class A GPCR superfamily is highly represented, and continued drug discovery for this family of receptors may provide novel therapeutics for a vast range of diseases. GPCR allosteric modulation is an innovative targeting approach that broadens the available small molecule toolbox and is proving to be a viable drug discovery strategy, as evidenced by recent FDA approvals and clinical trials. Numerous class A GPCR allosteric modulators have been discovered recently, and emerging trends such as the availability of GPCR crystal structures, diverse functional assays, and structure-based computational approaches are improving optimization and development. This Perspective provides an update on allosterically targeted class A GPCRs and their disease indications and the medicinal chemistry approaches toward novel allosteric modulators and highlights emerging trends and opportunities in the field.

| S-EPMC6556150 | biostudies-literature

Virtual screening of GPCRs: an in silico chemogenomics approach.

Project description:BACKGROUND: The G-protein coupled receptor (GPCR) superfamily is currently the largest class of therapeutic targets. In silico prediction of interactions between GPCRs and small molecules in the transmembrane ligand-binding site is therefore a crucial step in the drug discovery process, which remains a daunting task due to the difficulty to characterize the 3D structure of most GPCRs, and to the limited amount of known ligands for some members of the superfamily. Chemogenomics, which attempts to characterize interactions between all members of a target class and all small molecules simultaneously, has recently been proposed as an interesting alternative to traditional docking or ligand-based virtual screening strategies. RESULTS: We show that interaction prediction in the chemogenomics framework outperforms state-of-the-art individual ligand-based methods in accuracy both for receptor with known ligands and without known ligands. This is done with no knowledge of the receptor 3D structure. In particular we are able to predict ligands of orphan GPCRs with an estimated accuracy of 78.1%. CONCLUSION: We propose new methods for in silico chemogenomics and validate them on the virtual screening of GPCRs. The methods represent an extension of a recently proposed machine learning strategy, based on support vector machines (SVM), which provides a flexible framework to incorporate various information sources on the biological space of targets and on the chemical space of small molecules. We investigate the use of 2D and 3D descriptors for small molecules, and test a variety of descriptors for GPCRs. We show that incorporating information about the known hierarchical classification of the target family and about key residues in their inferred binding pockets significantly improves the prediction accuracy of our model.

| S-EPMC2553090 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data