Structure Of Receptor Research Articles

Synthesis of novel Cu(II) complexes with N2O2 ligands: Characterization, theoretical calculations, antimicrobial, antioxidant, DNA binding, and in vitro anticancer activity studies

The aim was to investigate the in vitro antimicrobial, antioxidant, cytotoxic activities and pBR322 Plasmid DNA interaction potentials of newly synthesized Schiff bases and their copper complexes. Cytotoxic activities of these compounds were determined by MTT methods in human breast cancer (MCF-7), human cervical cancer (HeLa) and mouse fibroblast (L929) cell lines. The determination of changes in oxidant and antioxidant load of the cell after application of these compounds were investigated with the aid of Rel Assay Diagnostics kits. It was found that the some of the compounds had moderate antimicrobial activity, and oxidative stress index. According to plasmid DNA interaction studies, synthesized complexes modified the tertiary structure of pBR322 plasmid DNA. The compound Bis-Napht showed the highest cytotoxic activity in HeLa, MCF-7 and L929 cells at an IC50 dose of 3 ± 1 µM, 5 ± 1 µM and 3 ± 1 µM respectively. Compound Bis-Sal was determined to have lower cytotoxic activity in L-929 cells at an IC50 dose of 106 ± 9 µM at 24 h compared to other compounds. Ligand compounds and their metal complexes were optimized on the B3LYP, HF, and M06-2x methods with the 6–31++g(d,p) basis set. Afterwards, their activities were compared against crystal structure of the BRCT repeat region from the breast cancer associated protein, (BRCA1) (PDB ID: 1JNX) and crystal Structure of CDK2 receptor of cervical cancer cell proteins (PDB ID: 4BGH). To examine the interactions occurring in more detail, Protein-Ligand Interaction Profiler analysis was performed and all chemical interactions that occurred were determined.

CXCR4-Targeted Radiopharmaceuticals for the Imaging and Therapy of Malignant Tumors.

C-X-C chemokine receptor type 4 (CXCR4), also known as fusin or CD184, is a 7-transmembrane helix G-protein-coupled receptor that is encoded by the CXCR4 gene. Involved in various physiological processes, CXCR4 could form an interaction with its endogenous partner, chemokine ligand 12 (CXCL12), which is also named SDF-1. In the past several decades, the CXCR4/CXCL12 couple has attracted a large amount of research interest due to its critical functions in the occurrence and development of refractory diseases, such as HIV infection, inflammatory diseases, and metastatic cancer, including breast cancer, gastric cancer, and non-small cell lung cancer. Furthermore, overexpression of CXCR4 in tumor tissues was shown to have a high correlation with tumor aggressiveness and elevated risks of metastasis and recurrence. The pivotal roles of CXCR4 have encouraged an effort around the world to investigate CXCR4-targeted imaging and therapeutics. In this review, we would like to summarize the implementation of CXCR4-targeted radiopharmaceuticals in the field of various kinds of carcinomas. The nomenclature, structure, properties, and functions of chemokines and chemokine receptors are briefly introduced. Radiopharmaceuticals that could target CXCR4 will be described in detail according to their structure, such as pentapeptide-based structures, heptapeptide-based structures, nonapeptide-based structures, etc. To make this review a comprehensive and informative article, we would also like to provide the predictive prospects for the CXCR4-targeted species in future clinical development.

Adenosine A2A Receptor (A2AAR) Ligand Screening Using the 19F-NMR Probe FPPA.

The binding affinity of G protein-coupled receptor (GPCR) ligands is customarily measured by radio-ligand competition experiments. As an alternative approach, 19F nuclear magnetic resonance spectroscopy (19F-NMR) is used for the screening of small-molecule lead compounds in drug discovery; the two methods are complementary in that the measurements are performed with widely different experimental conditions. Here, we used the structure of the A2A adenosine receptor (A2AAR) complex with V-2006 (3-(4-amino-3-methylbenzyl)-7-(furan-2-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine) as the basis for the design of a fluorine-containing probe molecule, FPPA (4-(furan-2-yl)-7-(4-(trifluoromethyl)benzyl)-7H-pyrrolo[2,3-d]pyramidin-2-amine), for binding studies with A2AAR. A protocol of experimental conditions for drug screening and measurements of drug binding affinities using 1D 19F-NMR observation of FPPA is validated with studies of known A2AAR ligands. 19F-NMR with FPPA is thus found to be a robust approach for the discovery of ligands with new core structures, which will expand the libraries of A2AAR-targeting drug candidates.

Design, Synthesis, and Computational Studies with ADMET of Novel Cardiovascular Hybrid Drugs

Recently the drug discovery trend has been to design hybrid drug molecules consisting of different pharmacophore groups linked together via spacers. Calcium channel blockers have an important role in the treatment of several cardiovascular diseases. The objective of the present research work is to encompass the strategic design, synthesis, and computational assessment of novel 1,4- dihydropyridine containing calcium channel blocker hybrid containing beta blocker side chain along with NO group as promoting cardiovascular agents as a viable alternative to well-established drugs like Amlodipine, Nifedipine, Felodipine, etc. In this research, we synthesized new 18 cardiovascular hybrid compounds based on structure-activity relationship properties. The 3D crystallographic structure of the calcium channel receptor (6M7H) was obtained from PDB. RCSB and used for docking study. The molecular docking studies were carried out by using the standard option Glide 5.5 in Maestro. In silico molecular docking analysis of all the synthesized compounds, AE1 to AE18, showed good docking scores and remarkable interactions with the essential amino acid residues located within the receptor's binding pocket of 6M7H. In comparison to amlodipine, AE12, AE6, AE8, AE11, AE5, AE16, and AE14 exhibit good scores as well as good binding patterns. AE12 exhibits the highest docking score of -8.455 kcal mol?1. Extensive ADMET profiling and structure–activity relationship (SAR) elucidated favorable pharmacokinetic properties and essential structural modifications influencing antihypertensive effectiveness.

Crystal structure of adenosine A2A receptor in complex with clinical candidate Etrumadenant reveals unprecedented antagonist interaction

The Gs protein-coupled adenosine A2A receptor (A2AAR) represents an emerging drug target for cancer immunotherapy. The clinical candidate Etrumadenant was developed as an A2AAR antagonist with ancillary blockade of the A2BAR subtype. It constitutes a unique chemotype featuring a poly-substituted 2-amino-4-phenyl-6-triazolylpyrimidine core structure. Herein, we report two crystal structures of the A2AAR in complex with Etrumadenant, obtained with differently thermostabilized A2AAR constructs. This led to the discovery of an unprecedented interaction, a hydrogen bond of T883.36 with the cyano group of Etrumadenant. T883.36 is mutated in most A2AAR constructs used for crystallization, which has prevented the discovery of its interactions. In-vitro characterization of Etrumadenant indicated low selectivity versus the A1AR subtype, which can be rationalized by the structural data. These results will facilitate the future design of AR antagonists with desired selectivity. Moreover, they highlight the advantages of the employed A2AAR crystallization construct that is devoid of ligand binding site mutations.

Structural analysis of a hormone-bound Striga strigolactone receptor.

Strigolactones (SLs) regulate many aspects of plant development, but ambiguities remain about how this hormone is perceived because SL-complexed receptor structures do not exist. We find that when SL binds the Striga receptor, ShHTL5, a series of conformational changes relative to the unbound state occur, but these events are not sufficient for signalling. Ligand-complexed receptors, however, form internal tunnels that posit an explanation for how SL exits its receptor after hydrolysis.

Molecular and biophysical features of hippocampal "lipid rafts aging" are modified by dietary n-3 long-chain polyunsaturated fatty acids.

"Lipid raft aging" in nerve cells represents an early event in the development of aging-related neurodegenerative diseases, such as Alzheimer's disease. Lipid rafts are key elements in synaptic plasticity, and their modification with aging alters interactions and distribution of signaling molecules, such as glutamate receptors and ion channels involved in memory formation, eventually leading to cognitive decline. In the present study, we have analyzed, in vivo, the effects of dietary supplementation of n-3 LCPUFA on the lipid structure, membrane microviscosity, domain organization, and partitioning of ionotropic and metabotropic glutamate receptors in hippocampal lipid raffs in female mice. The results revealed several lipid signatures of "lipid rafts aging" in old mice fed control diets, consisting in depletion of n-3 LCPUFA, membrane unsaturation, along with increased levels of saturates, plasmalogens, and sterol esters, as well as altered lipid relevant indexes. These changes were paralleled by increased microviscosity and changes in the raft/non-raft (R/NR) distribution of AMPA-R and mGluR5. Administration of the n-3 LCPUFA diet caused the partial reversion of fatty acid alterations found in aged mice and returned membrane microviscosity to values found in young animals. Paralleling these findings, lipid rafts accumulated mGluR5, NMDA-R, and ASIC2, and increased their R/NR proportions, which collectively indicate changes in synaptic plasticity. Unexpectedly, this diet also modified the lipidome and dimension of lipid rafts, as well as the domain redistribution of glutamate receptors and acid-sensing ion channels involved in hippocampal synaptic plasticity, likely modulating functionality of lipid rafts in memory formation and reluctance to age-associated cognitive decline.

A viscosity-sensitive and mitochondria-targeted AIEgen effectuated fatty liver imaging and cancer photodynamic therapy

The mitochondrial targeting and viscosity-sensitive near-infrared fluorescence probe TQS-OH was an aggregation induced emission luminogen constructed by regulating the receptor structure and hydroxylating its terminal. TQS-OH presented more than 27.35-fold fluorescence enhancement at the maximum emission peak when the viscosity level increased from 0.49 to 1048 cP. It also appeared excellent reactive oxygen species production ability under white light irradiation and appeared strong photodynamic therapied effect on HepG2 cells. In addition, cellular co-location analysis implied that TQS-OH had accurate mitochondrial targeting ability, with co-location coefficient up to 0.95 in human hepatocellular carcinoma HepG2 cells and it also successfully achieved fatty liver imaging. Meanwhile, we found that TQS-OH induced cancer cell apoptosis by activating mitochondrial apoptosis pathway. Furthermore, TQS-OH ultimately has implemented the tumor photodynamic therapy with high efficiency in vivo, with a tumor inhibition rate as high as 50.77%. The above results made it a promising aggregation induced emission material for the diagnosis of fatty liver and tumor phototherapy.

ImmuneBuilder: Deep-Learning models for predicting the structures of immune proteins

Immune receptor proteins play a key role in the immune system and have shown great promise as biotherapeutics. The structure of these proteins is critical for understanding their antigen binding properties. Here, we present ImmuneBuilder, a set of deep learning models trained to accurately predict the structure of antibodies (ABodyBuilder2), nanobodies (NanoBodyBuilder2) and T-Cell receptors (TCRBuilder2). We show that ImmuneBuilder generates structures with state of the art accuracy while being far faster than AlphaFold2. For example, on a benchmark of 34 recently solved antibodies, ABodyBuilder2 predicts CDR-H3 loops with an RMSD of 2.81Å, a 0.09Å improvement over AlphaFold-Multimer, while being over a hundred times faster. Similar results are also achieved for nanobodies, (NanoBodyBuilder2 predicts CDR-H3 loops with an average RMSD of 2.89Å, a 0.55Å improvement over AlphaFold2) and TCRs. By predicting an ensemble of structures, ImmuneBuilder also gives an error estimate for every residue in its final prediction. ImmuneBuilder is made freely available, both to download (https://github.com/oxpig/ImmuneBuilder) and to use via our webserver (http://opig.stats.ox.ac.uk/webapps/newsabdab/sabpred). We also make available structural models for ~150 thousand non-redundant paired antibody sequences (https://doi.org/10.5281/zenodo.7258553).

Structural Insights into Molecular Recognition and Receptor Activation in Chemokine-Chemokine Receptor Complexes.

The chemokine system is a key player in the functioning of the immune system and a sought-after target for drug candidates. The number of experimental structures of chemokines in complex with chemokine receptors has increased rapidly over the past few years, providing essential information for rational development of chemokine receptor ligands. Here, we perform a comparative analysis of all chemokine-chemokine receptor structures, with the aim of characterizing the molecular recognition processes and highlighting the relationships between chemokine structures and functional processes. The structures show conserved interaction patterns between the chemokine core and the receptor N-terminus, while interactions near ECL2 display subfamily-specific features. Detailed analyses of the interactions of the chemokine N-terminal domain in the 7TM cavities reveal activation mechanisms for CCR5, CCR2, and CXCR2 and a mechanism for biased agonism in CCR1.

Selective polypeptide ligand binding to the extracellular surface of the transmembrane domains of the class B GPCRs GLP-1R and GCGR

Crystal and cryo-EM structures of the glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) bound with their peptide ligands have been obtained with full-length constructs, indicating that the extracellular domain (ECD) is indispensable for specific ligand binding. This article complements these data with studies of ligand recognition of the two receptors in solution. Paramagnetic NMR relaxation enhancement measurements using dual labeling with fluorine-19 probes on the receptor and nitroxide spin labels on the peptide ligands provided new insights. The glucagon-like peptide-1 (GLP-1) was found to interact with GLP-1R by selective binding to the extracellular surface. The ligand selectivity toward the extracellular surface of the receptor was preserved in the transmembrane domain (TMD) devoid of the ECD. The dual labeling approach further provided evidence of cross-reactivity of GLP-1R and GCGR with glucagon and GLP-1, respectively, which is of interest in the context of medical treatments usingcombinations of the two polypeptides.

Function and Role of Histamine H1 Receptor in the Mammalian Heart.

Histamine can change the force of cardiac contraction and alter the beating rate in mammals, including humans. However, striking species and regional differences have been observed. Depending on the species and the cardiac region (atrium versus ventricle) studied, the contractile, chronotropic, dromotropic, and bathmotropic effects of histamine vary. Histamine is present and is produced in the mammalian heart. Thus, histamine may exert autocrine or paracrine effects in the mammalian heart. Histamine uses at least four heptahelical receptors: H1, H2, H3 and H4. Depending on the species and region studied, cardiomyocytes express only histamine H1 or only histamine H2 receptors or both. These receptors are not necessarily functional concerning contractility. We have considerable knowledge of the cardiac expression and function of histamine H2 receptors. In contrast, we have a poor understanding of the cardiac role of the histamine H1 receptor. Therefore, we address the structure, signal transduction, and expressional regulation of the histamine H1 receptor with an eye on its cardiac role. We point out signal transduction and the role of the histamine H1 receptor in various animal species. This review aims to identify gaps in our knowledge of cardiac histamine H1 receptors. We highlight where the published research shows disagreements and requires a new approach. Moreover, we show that diseases alter the expression and functional effects of histamine H1 receptors in the heart. We found that antidepressive drugs and neuroleptic drugs might act as antagonists of cardiac histamine H1 receptors, and believe that histamine H1 receptors in the heart might be attractive targets for drug therapy. The authors believe that a better understanding of the role of histamine H1 receptors in the human heart might be clinically relevant for improving drug therapy.

Virtual Screening Algorithms in Drug Discovery: A Review Focused on Machine and Deep Learning Methods

Drug discovery and repositioning are important processes for the pharmaceutical industry. These processes demand a high investment in resources and are time-consuming. Several strategies have been used to address this problem, including computer-aided drug design (CADD). Among CADD approaches, it is essential to highlight virtual screening (VS), an in silico approach based on computer simulation that can select organic molecules toward the therapeutic targets of interest. The techniques applied by VS are based on the structure of ligands (LBVS), receptors (SBVS), or fragments (FBVS). Regardless of the type of VS to be applied, they can be divided into categories depending on the used algorithms: similarity-based, quantitative, machine learning, meta-heuristics, and other algorithms. Each category has its objectives, advantages, and disadvantages. This review presents an overview of the algorithms used in VS, describing them and showing their use in drug design and their contribution to the drug development process.

APJ as Promising Therapeutic Target of Peptide Analogues in Myocardial Infarction- and Hypertension-Induced Heart Failure.

The widely expressed G protein-coupled apelin receptor (APJ) is activated by two bioactive endogenous peptides, apelin and ELABELA (ELA). The apelin/ELA-APJ-related pathway has been found involved in the regulation of many physiological and pathological cardiovascular processes. Increasing studies are deepening the role of the APJ pathway in limiting hypertension and myocardial ischaemia, thus reducing cardiac fibrosis and adverse tissue remodelling, outlining APJ regulation as a potential therapeutic target for heart failure prevention. However, the low plasma half-life of native apelin and ELABELA isoforms lowered their potential for pharmacological applications. In recent years, many research groups focused their attention on studying how APJ ligand modifications could affect receptor structure and dynamics as well as its downstream signalling. This review summarises the novel insights regarding the role of APJ-related pathways in myocardial infarction and hypertension. Furthermore, recent progress in designing synthetic compounds or analogues of APJ ligands able to fully activate the apelinergic pathway is reported. Determining how to exogenously regulate the APJ activation could help to outline a promising therapy for cardiac diseases.

Sensitive and Selective Electrochemical Determination of Thrombin as a Peptide Biomarker by a Multiwalled Carbon Nanotube (MWCNT)/Aptamer/Molecularly Imprinted Polymer (MIP)-Based Biosensor

Molecularly imprinted polymer (MIP) and DNA aptamers detect targets with high sensitivity and specificity, simulating the structure and function of antibodies and biological receptors. The combination of MIPs and aptamers is being an excellent way to create hybrid alternatives with enhanced attributes and desirable properties. With this motivation, a new method has been developed to produce aptamer/MIP hybrids for protein biomarkers that is simple and reproducible. In addition, multi-walled carbon nanotubes (MWCNTs) were used because of their outstanding chemical/mechanical stability to develop sensitive sensor/biosensors. The MWCNTs/Aptamer/MIP system was characterized using cyclic voltammetry (CV), differential pulse voltammetry (DPV), and electrochemical impedance spectroscopy (EIS). Furthermore, atomic force microscopy (AFM) was used for morphological characterization. Thrombin was used as a model peptide for this system with a linear response from 5 pg/mL to 150 pg/mL and a detection limit of 1.4 pg/mL. The system was also tested for selectivity, stability, and practical analysis and showed satisfactory results compared to the literature.

Changes in dopamine and octopamine levels caused disordered behaviour in red imported fire ants exposed to cinnamon essential oils

Some plant essential oils (EOs) are environmentally friendly insecticides because they can kill insects by manipulating the social behaviour of the red imported fire ants. In this study, we found that the main component of cinnamon oil, trans-cinnamaldehyde, which is extracted from the bark and leaves of Cinnamomum loureirii Nees and Cinnamomum cassia Presl, could cause leg-antennal and double-antennal grooming, as well as fighting behaviors in red imported fire ants. In particular, the bark oils not only produced strong fighting behaviour but also accelerated the death of the worker ants. Analysis of the contents of neurotransmitters (octopamine and dopamine) in red imported fire worker ants treated with trans-cinnamaldehyde, the main component of cinnamon oil, showed that trans-cinnamaldehyde destroyed the antennal receptor structure, causing a decrease in octopamine content and in the ants' ability to recognise their nest mates. Trans-cinnamaldehyde stimulated the synthesis of dopamine, thereby enhancing the aggression of the worker ants. Indeed, the relative mRNA expression levels of two genes needed for dopamine synthesis, tyrosine hydroxylase and DOPA decarboxylase, were significantly upregulated compared with those of the control group (CK) from the beginning of the fight to the peak of the fight. The ratio of octopamine to dopamine reached 1:86 during the peak of the fight. The findings revealed that trans-cinnamaldehyde acts on the nervous system of red imported fire ants to interfere with the behaviour of the workers, thus providing a strategy to control the spread of red imported fire ants using cinnamon EOs.

Modeling the SARS-CoV-2 receptor ACE2 indicates that protein-bound Zn affects distant protein stability and interactions

Abstract Molecular Dynamics (MD) is a widely used drug design tool capable of rapidly screening the binding capacity of many candidate inhibitors in a cost-effective manner. This approach has been leveraged to search for molecules that can bind to angiotensin converting enzyme 2 (ACE2) and prevent SARS-CoV-2 viral entry to host cells. However, ACE2 is difficult to model due to an embedded zinc ion (Zn), which introduces complex charge transfer and polarization. Since the embedded Zn is distant from the site of ACE2 binding, many groups have assumed Zn does not impact protein interactions and have excluded Zn while modeling ACE2. Here, we evaluated the impact of Zn by performing MD simulations of Zn-bound and Zn-free versions of the ACE2-spike protein (S1) and ACE2-monoclonal antibody (mAb) systems . We found that excluding Zn had a significant effect on total protein stability and the stability of interacting residues, indicating that Zn can impact distant protein sites. Additionally, we discovered that including protein-bound Zn in MD simulations improved the binding free energy of both systems by −3.26 and −14.8 kcal/mol in the ACE2-S1 and ACE2-mAb systems, respectively. These data suggest that excluding Zn may alter inhibitor selection decisions and should be included for accurate modeling. Interestingly, ACE2-mAb is particularly sensitive to changes in receptor structure, likely reflecting its generation against in vivo Zn-bound ACE2. Collectively, our data demonstrates that excluding Zn significantly impacts MD simulation outcomes which inform inhibitor selection, particularly when modeling receptor-mAb complexes.

Control of Synaptic Levels of Nicotinic Acetylcholine Receptor by the Sequestering Subunit Dα5 and Secreted Scaffold Protein Hig.

The presentation of nicotinic acetylcholine receptors (nAChRs) on synaptic membranes is crucial for generating cholinergic circuits, some of which are associated with memory function and neurodegenerative disorders. Although the physiology and structure of nAChR, a cation channel comprising five subunits, have been extensively studied, little is known about how the receptor levels in interneuronal synapses are determined and which nAChR subunits participate in the regulatory process in cooperation with synaptic cleft matrices and intracellular proteins. By a genetic screen of Drosophila, we identified mutations in the nAChR subunit Dα5 gene as suppressors that restored the mutant phenotypes of hig, which encodes a secretory matrix protein localized to cholinergic synaptic clefts in the brain. Only the loss of function of Dα5 among the 10 nAChR subunits suppressed hig mutant phenotypes in both male and female flies. Dα5 behaved as a lethal factor when Hig was defective; loss of Dα5 in hig mutants rescued lethality, upregulating Dα6 synaptic levels. By contrast, levels of Dα5, Dα6, and Dα7 subunits were all reduced in hig mutants. These three subunits have distinct properties for interaction with Hig or trafficking, as confirmed by chimeric subunit experiments. Notably, the chimeric Dα5 protein, which has the extracellular sequences that display no positive interaction with Hig, exhibited abnormal distribution and lethality even in the presence of Hig. We propose that the sequestering subunit Dα5 functions by reducing synaptic levels of nAChR through internalization, and this process is blocked by Hig, which tethers Dα5 to the synaptic cleft matrix.SIGNIFICANCE STATEMENT Because the cholinergic synapse is one of the major synapses that generate various brain functions, numerous studies have sought to reveal the physiology and structure of the nicotinic acetylcholine receptor (nAChR). However, little is known about how synaptic levels of nAChR are controlled and which nAChR subunits participate in the regulatory process in cooperation with synaptic cleft matrices. By a genetic screen of Drosophila, we identified mutations in the nAChR subunit Dα5 gene as suppressors that restored the mutant phenotypes of hig, which encodes a secretory matrix protein localized to cholinergic synaptic clefts. Our data indicate that Dα5 functions in reducing synaptic levels of nAChR, and this process is blocked by Hig, which tethers Dα5 to the synaptic cleft matrix.

Leukotriene receptors in GtoPdb v.2023.1

The leukotriene receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Leukotriene Receptors [35, 38]) are activated by the endogenous ligands leukotrienes (LT), synthesized from lipoxygenase metabolism of arachidonic acid. The human BLT1 receptor is the high affinity LTB4 receptor whereas the BLT2 receptor in addition to being a low-affinity LTB4 receptor also binds several other lipoxygenase-products, such as 12S-HETE, 12S-HPETE, 15S-HETE, and the thromboxane synthase product 12-hydroxyheptadecatrienoic acid. The BLT receptors mediate chemotaxis and immunomodulation in several leukocyte populations and are in addition expressed on non-myeloid cells, such as vascular smooth muscle and endothelial cells. In addition to BLT receptors, LTB4 has been reported to bind to the peroxisome proliferator activated receptor (PPAR) α [201] and the vanilloid TRPV1 ligand-gated nonselective cation channel [223]. The crystal structure of the BLT1 receptor was initially determined in complex with selective antagonists [141, 231] and has recently been extended to the cryo-electron microscopy structure of LTB4-bound human BLT1 receptor at 2.91 Å resolution [389]. The receptors for the cysteinyl-leukotrienes (i.e. LTC4, LTD4 and LTE4) are termed CysLT1 and CysLT2 and exhibit distinct expression patterns in human tissues, mediating for example smooth muscle cell contraction, regulation of vascular permeability, and leukocyte activation. Quite recently, the the crystal structures of both receptors have been solved, the CysLT1 in complex with zafirlukast and pranlukast [203] and the CysLT2 in complex with three dual CysLT1/CysLT2 antagonists [122]. There is also evidence in the literature for additional CysLT receptor subtypes, derived from functional in vitro studies, radioligand binding and in mice lacking both CysLT1 and CysLT2 receptors [38]. Cysteinyl-leukotrienes have also been suggested to signal through the P2Y12 receptor [99, 251, 280], GPR17 [60] and GPR99 [173].

Adenosine receptors in GtoPdb v.2023.1

Adenosine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Adenosine Receptors [112]) are activated by the endogenous ligand adenosine (potentially inosine also at A3 receptors). Crystal structures for the antagonist-bound [155, 316, 224, 62], agonist-bound [379, 205, 206] and G protein-bound A2A adenosine receptors [49] have been described. The structures of an antagonist-bound A1 receptor [130] and an adenosine-bound A1 receptor-Gi complex [87] have been resolved by cryo-electronmicroscopy. Another structure of an antagonist-bound A1 receptor obtained with X-ray crystallography has also been reported [58]. The structure of the A2B receptor has also been elucidated [57]. caffeine is a nonselective antagonist for adenosine receptors, while istradefylline, a selective A2A receptor antagonist, is on the market for the treatment of Parkinson's disease.