scholarly journals DEER Analysis of GPCR Conformational Heterogeneity

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 778
Author(s):  
Matthias Elgeti ◽  
Wayne L. Hubbell
Keyword(s):  
Rational Design ◽  
Loose Coupling ◽  
Ligand Affinity ◽  
Pharmacological Targets ◽  
Recent Developments ◽  
Therapeutic Molecules ◽  
Helical Proteins ◽  
Site Directed Spin Labeling ◽  
Double Electron Electron Resonance ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) represent a large class of transmembrane helical proteins which are involved in numerous physiological signaling pathways and therefore represent crucial pharmacological targets. GPCR function and the action of therapeutic molecules are defined by only a few parameters, including receptor basal activity, ligand affinity, intrinsic efficacy and signal bias. These parameters are encoded in characteristic receptor conformations existing in equilibrium and their populations, which are thus of paramount interest for the understanding of receptor (mal-)functions and rational design of improved therapeutics. To this end, the combination of site-directed spin labeling and EPR spectroscopy, in particular double electron–electron resonance (DEER), is exceedingly valuable as it has access to sub-Angstrom spatial resolution and provides a detailed picture of the number and populations of conformations in equilibrium. This review gives an overview of existing DEER studies on GPCRs with a focus on the delineation of structure/function frameworks, highlighting recent developments in data analysis and visualization. We introduce “conformational efficacy” as a parameter to describe ligand-specific shifts in the conformational equilibrium, taking into account the loose coupling between receptor segments observed for different GPCRs using DEER.

Recent developments and opportunities in fighting COVID-19

Coronaviruses ◽  
2020 ◽  
Vol 01 ◽  
Author(s):  
Vikram Rao ◽  
Subrat Kumar Bhattamisra
Keyword(s):  
World Health ◽  
Diagnostic Tools ◽  
Extensive Literature ◽  
Angiotensin Converting Enzyme 2 ◽  
Recent Developments ◽  
Therapeutic Molecules ◽  
Discharged Patients ◽  
Extensive Literature Search ◽  
Repurposed Drugs ◽  
Health Organization

Background: COVID-19, a Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2) was first diagnosed in the patients from Wuhan, China in December 2019. Within couple of months of infection, it was declared as pandemic by World health organization. COVID-19 has become the most contagious infection with a serious threat to global health. In this review, we aimed to discuss the pathogenesis, diagnostics, current treatments and potential vaccines for COVID-19. Methods: An extensive literature search was conducted using keywords “COVID-19”; “Coronavirus”; “SARS-Cov-2”; “SARS” in public domains of Google, Google scholar, PubMed, and ScienceDirect. Selected articles were used to construct this review. Results: SARS-Cov-2 uses the Spike (S) protein on its surface to recognize the receptor on angiotensin-converting enzyme 2 (ACE2) and bind with 10-folds greater affinity than SARS-Cov-1. Molecular assays and immunoassays are the most frequently used tests whereas computed tomography (CT) scans, Artificial intelligence enabled diagnostic tools were also used in patients. In therapeutic treatment, few drugs were repurposed and there are 23 therapeutic molecules including the repurposed drugs are in different stages of clinical trial. Similarly, development of vaccines is also in the pipeline. Few countries have managed well to contain the spread by rapid testing and identifying the clusters. Conclusion: Till now, the acute complications and mortality of COVID-19 has been linked to the pre-existing comorbid conditions or age. Besides the development of therapeutic strategies that includes drugs and vaccine, the long term implication of COVID-19 infection in terms of the disorder/disability in the cured/discharged patients is a new area to investigate.

scholarly journals Endogenous and exogenous electric fields as modifiers of brain activity: rational design of noninvasive brain stimulation with transcranial alternating current stimulation

2014 ◽  
Vol 16 (1) ◽  
pp. 93-102 ◽  
Keyword(s):  
Electric Fields ◽  
Brain Stimulation ◽  
Rational Design ◽  
Brain Activity ◽  
Field Potential ◽  
Alternating Current ◽  
Noninvasive Brain Stimulation ◽  
Starting Point ◽  
Recent Developments ◽  
Transcranial Alternating Current Stimulation

Synchronized neuronal activity in the cortex generates weak electric fields that are routinely measured in humans and animal models by electroencephalography and local field potential recordings. Traditionally, these endogenous electric fields have been considered to be an epiphenomenon of brain activity. Recent work has demonstrated that active cortical networks are surprisingly susceptible to weak perturbations of the membrane voltage of a large number of neurons by electric fields. Simultaneously, noninvasive brain stimulation with weak, exogenous electric fields (transcranial current stimulation, TCS) has undergone a renaissance due to the broad scope of its possible applications in modulating brain activity for cognitive enhancement and treatment of brain disorders. This review aims to interface the recent developments in the study of both endogenous and exogenous electric fields, with a particular focus on rhythmic stimulation for the modulation of cortical oscillations. The main goal is to provide a starting point for the use of rational design for the development of novel mechanism-based TCS therapeutics based on transcranial alternating current stimulation, for the treatment of psychiatric illnesses.

scholarly journals Dopamine D3 Receptor Heteromerization: Implications for Neuroplasticity and Neuroprotection

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 1016 ◽  
Author(s):  
Federica Bono ◽  
Veronica Mutti ◽  
Chiara Fiorentini ◽  
Cristina Missale
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Neuronal Development ◽  
G Protein Coupled Receptors ◽  
D3 Receptor ◽  
Pharmacological Targets ◽  
Receptor Heteromers ◽  
Dopamine D3 ◽  
Functional Features ◽  
G Protein Coupled

The dopamine (DA) D3 receptor (D3R) plays a pivotal role in the control of several functions, including motor activity, rewarding and motivating behavior and several aspects of cognitive functions. Recently, it has been reported that the D3R is also involved in the regulation of neuronal development, in promoting structural plasticity and in triggering key intracellular events with neuroprotective potential. A new role for D3R-dependent neurotransmission has thus been proposed both in preserving DA neuron homeostasis in physiological conditions and in preventing pathological alterations that may lead to neurodegeneration. Interestingly, there is evidence that nicotinic acetylcholine receptors (nAChR) located on DA neurons also provide neurotrophic support to DA neurons, an effect requiring functional D3R and suggesting the existence of a positive cross-talk between these receptor systems. Increasing evidence suggests that, as with the majority of G protein-coupled receptors (GPCR), the D3R directly interacts with other receptors to form new receptor heteromers with unique functional and pharmacological properties. Among them, we recently identified a receptor heteromer containing the nAChR and the D3R as the molecular effector of nicotine-mediated neurotrophic effects. This review summarizes the functional and pharmacological characteristics of D3R, including the capability to form active heteromers as pharmacological targets for specific neurodegenerative disorders. In particular, the molecular and functional features of the D3R-nAChR heteromer will be especially discussed since it may represent a possible key etiologic effector for DA-related pathologies, such as Parkinson’s disease (PD), and a target for drug design.

Metalloligand Strategies for Assembling Heteronuclear Nanocages – Recent Developments

2019 ◽  
Vol 72 (10) ◽  
pp. 731 ◽  
Author(s):  
Feng Li ◽  
Leonard F. Lindoy
Keyword(s):  
Structural Properties ◽  
Metal Ion ◽  
Rational Design ◽  
Building Blocks ◽  
Structural Elements ◽  
Present Discussion ◽  
The Past ◽  
Recent Developments ◽  
Metal Organic ◽  
Multifunctional Ligand

The use of metalloligands as building blocks for the assembly of metallo-organic cages has received increasing attention over the past two decades or so. In part, the popularity of this approach reflects its stepwise nature that lends itself to the predesigned construction of metallocages and especially heteronuclear metallocages. The focus of the present discussion is on the use of metalloligands for the construction of discrete polyhedral cages, very often incorporating heterometal ions as structural elements. The metalloligand approach uses metal-bound multifunctional ligand building blocks that display predesigned structural properties for coordination to a second metal ion such that the rational design and construction of both homo- and heteronuclear metal–organic cages are facilitated. The present review covers published literature in the area from early 2015 to early 2019.

scholarly journals Thermostability of a recombinant G protein-coupled receptor expressed at high level in mammalian cell culture

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Alexei Yeliseev ◽  
Arjen van den Berg ◽  
Lioudmila Zoubak ◽  
Kirk Hines ◽  
Sam Stepnowski ◽  
...  
Keyword(s):  
G Protein ◽  
Mammalian Cell ◽  
Rational Design ◽  
Mammalian Cell Culture ◽  
High Yield ◽  
Pharmaceutical Drugs ◽  
C Terminus ◽  
Mammalian Cell Cultures ◽  
High Level ◽  
G Protein Coupled

Abstract Rational design of pharmaceutical drugs targeting integral membrane G protein-coupled receptors (GPCR) requires thorough understanding of ligand binding and mechanism of activation through high resolution structural studies of purified proteins. Due to inherent conformational flexibility of GPCR, stabilization of these proteins solubilized from cell membranes into detergents is a challenging task. Here, we take advantage of naturally occurring post-translational modifications for stabilization of purified GPCR in detergent micelles. The recombinant cannabinoid CB2 receptor was expressed at high yield in Expi293F mammalian cell cultures, solubilized and purified in Façade detergent. We report superior stability of the mammalian cell-expressed receptor compared to its E.coli-expressed counterpart, due to contributions from glycosylation of the N terminus and palmitoylation of the C terminus of CB2. Finally, we demonstrate that the mammalian Expi293F amino acid labelling kit is suitable for preparation of multi-milligram quantities of high quality, selectively stable isotope-labeled GPCR for studies by nuclear magnetic resonance.

scholarly journals The Bewildering Antitubercular Action of Pyrazinamide

2020 ◽  
Vol 84 (2) ◽  
Author(s):  
Elise A. Lamont ◽  
Nicholas A. Dillon ◽  
Anthony D. Baughn
Keyword(s):  
Mode Of Action ◽  
Rational Design ◽  
Multidrug Resistant ◽  
Future Research ◽  
Therapeutic Approaches ◽  
Treatment Regimens ◽  
Tb Treatment ◽  
Short Course ◽  
Recent Developments ◽  
Susceptibility And Resistance

SUMMARY Pyrazinamide (PZA) is a cornerstone antimicrobial drug used exclusively for the treatment of tuberculosis (TB). Due to its ability to shorten drug therapy by 3 months and reduce disease relapse rates, PZA is considered an irreplaceable component of standard first-line short-course therapy for drug-susceptible TB and second-line treatment regimens for multidrug-resistant TB. Despite over 60 years of research on PZA and its crucial role in current and future TB treatment regimens, the mode of action of this unique drug remains unclear. Defining the mode of action for PZA will open new avenues for rational design of novel therapeutic approaches for the treatment of TB. In this review, we discuss the four prevailing models for PZA action, recent developments in modulation of PZA susceptibility and resistance, and outlooks for future research and drug development.

scholarly journals Recent advances in the rational synthesis and self-assembly of anisotropic plasmonic nanoparticles

2018 ◽  
Vol 90 (9) ◽  
pp. 1393-1407 ◽  
Author(s):  
Leonardo Scarabelli
Keyword(s):  
Self Assembly ◽  
Rational Design ◽  
Short Review ◽  
Cascade Reactions ◽  
Full Potential ◽  
Plasmonic Materials ◽  
Optical And Electronic Properties ◽  
Complex Architectures ◽  
Recent Developments ◽  
Surface Chemistries

Abstract The field of plasmonics has grown at an incredible pace in the last couple of decades, and the synthesis and self-assembly of anisotropic plasmonic materials remains highly dynamic. The engineering of nanoparticle optical and electronic properties has resulted in important consequences for several scientific fields, including energy, medicine, biosensing, and electronics. However, the full potential of plasmonics has not yet been realized due to crucial challenges that remain in the field. In particular, the development of nanoparticles with new plasmonic properties and surface chemistries could enable the rational design of more complex architectures capable of performing advanced functions, like cascade reactions, energy conversion, or signal transduction. The scope of this short review is to highlight the most recent developments in the synthesis and self-assembly of anisotropic metal nanoparticles, which are capable of bringing forward the next generation of plasmonic materials.

Sign in / Sign up

Export Citation Format

Share Document