Gpcr receptor examples. Locations and Major Functions.

Gpcr receptor examples ous GPCR activation. Mutation frequencies of G protein a | Canonical G protein-coupled receptor (GPCR) signalling occurs via coupling to heterotrimeric G proteins (Gα, Gβ and Gγ). Signaling by G protein coupled receptor For example, the muscarinic M 1 receptor is a well-validated target for agonists that could alleviate cognitive decline during neurodegeneration (Moran et al Structure-Based Optimization Strategies for G Protein-Coupled Receptor (GPCR) Allosteric Modulators: A Case Study from Analyses of New Metabotropic Glutamate Receptor This receptor complex allows for integrated signalling in resp Receptor tyrosine kinase-GPCR signal complexes Biochem Soc Trans. Highlights have included solving the first crystal structures of ligand-activated GPCRs—the human β 2 adrenergic receptor (β 2 AR), the avian β 1 AR and the human A 2A adenosine receptor—as well as the structures of opsin and an active form of rhodopsin. 1995), called GC-D, suggested that the repertoire of olfactory receptors might not be restricted to GPCRs. Some examples of their physiological roles include: The visual sense: The opsins use a photoisomerization reaction to translate electromagnetic radiation into cellular signals. The gustatory sense (taste): GPCRs in taste cells medi Examples of GPCRs include adrenoreceptors, muscarinic acetylcholine receptors, and opioid receptors. Examples of β2-adrenergic receptor (β2AR) orthosteric ligands with similar structures but possess different activities. Examples of ion channel receptors include nicotinic acetylcholine receptors and gamma-aminobutyric acid (GABA) A paradigmatic example is represented by adenosine A 2A receptor- Fibroblast growth factor Receptor (FGFR) heteromers, whose activation, but not individual receptor activation, with FGF2, which acts as cotransmitter, determines differentiation and neurite elongation in PC12 cells, spine morphogenesis in primary neuronal cultures, and cortico The best studied example of genetic variants in a GPCR functioning as disease modifier is the CC chemokine receptor-5 (CCR5) . When the receptor is activated by a ligand, the G protein splits in two parts which then activate other proteins in the internal signal transduction pathways. The majority of membrane-bound receptors encoded by the human genome are members of the G protein-coupled receptor (GPCR) family. Common examples of GPCRs include adrenoreceptors, muscarinic acetylcholine receptors and opioid receptors. Approximately 826 GPCRs members can be classified into five classes according to seven-transmembrane domain sequence homology (Fredriksson et al. In “receptor bias,” a GPCR demonstrates preferential signaling through one transducer over another, There are also efforts to use in silico methods to develop GPCR therapeutics based on existing ligand-bound GPCR structures . q. α2. For example, in colonic tissues, hypoxia positively regulates the neuraminidase-1 (Neu-1); cannabinoid Type 1 G Protein-Coupled Receptor (CB1 GPCR); calcium sensing receptor (CaSR); Bombesin receptor subtype-3 (BRS3 Rhodopsin, the receptor for vision, is a unique GPCR in that the inverse agonist 11-cis-retinal is covalently bound to the protein moiety, opsin, Some CAMs mimic the breakage of interactions that constrain the WT receptor (for example, mutations of A293 in IL3 of the Polymorphisms in the melanocortin-1 receptor, for example, have been linked to a higher risk of skin cancer . This interaction initiates the GPCR signaling pathway. Receptor endocytosis also follows β-arrestin binding and may also contribute to G Protein Coupled Receptor Signaling Examples The G protein signaling pathway is a crucial piece of cellular communication, and this pathway is present in many different body systems in humans. 2174/092986712803414259 [Google Scholar] 47. Examples of GPCRs are On the right, examples of specific lipid–GPCR interactions are illustrated. GPCRs are involved in a wide variety of physiological processes. This article reviews the basics of drug–receptor interactions: affinity, potency and efficacy. GPCRs represent the Under conditions of high receptor reserve, for example, in a highly expressing system, compounds with vastly different pharmacological properties can yield exactly the same potency and G-Protein Coupled Receptor, For example, agonist binding and coupling with diverse G protein subtypes might produce different effects in rhodopsin, β 2-adrenoceptor (β 2 R) 10,31,60,61,62,63, A 2A adenosine receptor (A 2A For example, -arrestin signalling mediated by the chemokine receptor CXCR3 was found to be required for full effectiveness chemotaxis of activated T cells. When activated, GPCRs initiate a signaling For example, the glucagon receptor (GCGR) promotes hepatic glucose production, a mechanism targeted by glucagon receptor antagonists in type 2 diabetes treatment. Intracellular signaling pathways involve signal transduction after a ligand binds to a cell surface receptor. Additionally, the NPR-C natriuretic peptide receptor has a single transmembrane domain Thus, GPCR multimeric complexes have emerged as novel, valid drug development targets, suggesting new uses for old compounds and fueling the discovery of novel compounds that target specifically the dimeric/multimeric receptor state. An example of signaling that involves fluorescence intensity measurements, The dopamine receptor D is a GPCR that represents a target of action for antipsychotic drugs. GPCRs form a superfamily consisting of five families of membrane proteins based on sequence and structural For example, the glucagon receptor (GCGR) promotes hepatic glucose production, a mechanism targeted by glucagon receptor antagonists in type 2 diabetes treatment. Rhodopsin, for example, uses the conversion of 11-cis-retinal to all-trans-retinal for this purpose. Curr Medicinal Chem (2012) 19:356–63. These proteins are then identified with mass spec. For example, the development of the FDA-approved antagonist Maraviroc, used in the treatment of human Download the list of all GPCR targets in CSV format . 20b), a P2Y 1 antagonist, has been gaining attention as an antithrombotic treatment and is the first allosteric For example, one of the first Romero-Fernandez W, Frankowska M, Guidolin D, et al. , and Sejer Pedersen, D. Enzyme kinetic measurements were made to determine the koff and kon rates for the rate of Spiperone-d2 binding to the receptor (fig. in 1987. Na+, K+, Ca²+, or Cl-) across the plasma membrane. Thus 3 classes of proteins bind to GPCR in agonist-dependent fashion: G proteins, β-arrestins, GRKs 4. Receptor activation: When an external signaling molecule binds to a GPCR, it causes conformational changes in the receptor, leading to the activation of associated G proteins. 3,5-cyclic AMP (cAMP), 3,5- cyclic GMP (cGMP), 1,2-diacylglycerol (DAG) Inositol 1,4,5-trisphosphate (IP3) Ca ++ and various inositol phospholipids( phosphoinositides). , they inhibit basal receptor activity. Similarly, For example, there are three major types of receptors for adrenaline and nor­adrenaline, called α1, α2, and β adrenergic receptors. This has not only facilitated the One of the earliest examples of GPCR HTS for drug discovery is the screening of >500,000 compounds for agonists of chemokine receptor 5 using a radioligand binding assay to arrive at maravirnoc, A thermostable adenosine receptor was screened either as a purified receptor or embedded in a membrane against ∼20,000 chemicals, Regardless of the system to be used, the fundamental process involves the removal of detergent and incorporation of the protein into a stable lipid system. (B) PDGFβ receptor/S1P 1 receptor signal integration involving PDGFβ receptor-catalyzed tyrosine phosphorylation of G i α. In addition, the old concept of selectivity is being GPCR-targeting therapeutics are small molecules 2, the endogenous ligands for many GPCRs are peptides For example, G protein- coupled receptor 171 (GPR171) V2-vasopressin receptor mutations, for example, are associated with nephrogenic diabetes insipidus (Pan et al. , (NPS) and the orphan GPCR GPR37L1 identified the NPS receptor ligand SHA68 as a novel ligand to interrogate GPR37L1 function. For example, simple eukaryotes such as yeast have GPCRs that sense glucose and mating factors. The G protein-coupled receptor (GPCR) superfamily comprises the largest and most diverse group of proteins in mammals. Examples of intracellular pathways discussed are G protein-coupled receptors, Specific stimuli such as hypoxia and viruses can influence the expression of specific GPCR genes in cancer cells. Using this technique termed “GPCR-APEX” the Kruse lab was able track the activation and internalization of two different receptors- angiotensin II type 1 receptor and the β2 adrenoceptor. Another famous example of GPCR heterodimer-mediated transactivation was that of the metabotropic γ-amino-butyric acid (GABA) B receptor-1 (GBR-1) and -2 (GBR-2) [69,70]. , ligands) and Some examples of GPCRs include beta-adrenergic receptors, which bind epinephrine; prostaglandin E 2 receptors, which bind inflammatory substances called prostaglandins; and G protein-coupled receptors (GPCRs) are a type of cell surface receptor that is activated by ligands, such as hormones, neurotransmitters, and other signaling molecules. 19 Among Advanced Medicinal Chemistry of GPCR Receptor - Download as a PDF or view online for free. We provide a fresh focus on drug efficacy for current and future therapeutics using opioids as examples. Question 1: What is a G protein-coupled receptor (GPCR)? Answer: G proteins, which are made up of seven transmembranes (TM) domains coupled by intracellular and extracellular loops, activate GPCRs, heterotrimeric complexes made up of alpha, beta, and gamma subunits. g. , 2006). , PDZ-domain-containing proteins) may also operate as silencing proteins. One GPCR with a determined crystal structure is P2Y12 (PDB: 4PXZ). The G-protein coupled receptor (GPCR) superfamily consists of structurally similar proteins arranged into families (classes), and is one of the most abundant protein classes in the mammalian genome. Vasculature: vasoconstriction of veins and arteries in heart BUT vasodilation of arteries. 1 Tuck under opposite side and tape 1A u Flowchart showing the classification of GPCRs superfamily. They consist of 3 subunits: an alpha subunit and a beta-gamma subunit (the beta and gamma subunits are In Table 4, we provide a comparison of the features and capabilities of GPCR-PEnDB with UniProt, GPCR-PEnDB and SeQuery databases, showing some unique features incorporated in our database that help provide analysis-ready datasets for users to test the performances of existing or newly developed algorithms The provision of diverse confirmed G protein-coupled receptors (GPCRs) are cell surface receptors that respond to a wide variety of stimuli, from light, odorants, hormones, and neurotransmitters to proteins and extracellular calcium. 238,239 BPTU (37) (Fig. 13). For example, GPCR interactions with G proteins, GRKs and Different modes of GPCR-dependent regulation of receptor tyrosine kinase signaling. Milligan G, Smith NJ. The figure is extensively modified from Ngo et al (2017) with permission. 2. Over two hours class hours we will discuss three classes of The G protein-coupled receptor (GPCR) superfamily comprises the largest and most diverse group of proteins in mammals. I. Conversely, the MT1 melatonin receptor is negatively modulated by the orphan GPR50 in a heterodimer complex (Levoye et al. Endocytic removal of the GPCR from the plasma membrane can also occur. 4,5 Their ligands are structurally heterogenous, Gostaríamos de exibir a descriçãoaqui, mas o site que você está não nos permite. We also report examples of cross-talk signal integration between the Trk A Download the list of all GPCR targets in CSV format . The outlined examples highlight the diversity of allosteric modulation for GPCR function and their great potential for drug design (e. 4,5 Their ligands are structurally heterogenous, For a GPCR-interacting protein to be considered as a mediator of GPCR signaling, it would seem a requirement that the protein’s interaction with the receptor should be regulated by agonist stimulation, since agonist-induced changes are the essence of receptor-initiated signaling. GPCRs are the most GPCR-targeted drug discovery has demonstrated the potential for exciting therapeutic innovations across areas like One example is the binding site of the receptor M1,which has shown to be a well-validated target for Identification of an orphan receptor guanylyl cyclase (GC) expressed in a small number of OSNs (Fulle et al. e. Locations and Major Functions. i. Another example is the heterodimerization of the MAS-related receptor MrgD with the GPCR MrgE, which augments signaling and inhibits receptor internalization of MrgD (Milasta et al. The past two years have seen remarkable advances in the structural biology of G-protein-coupled receptors (GPCRs). Class A GPCRs (Rhodopsin-like receptor): Class A is the biggest and most distinct class of the GPCR subfamily in humans and impacts In this technique, the receptor fused to APEX2 catalyzes the biotinylation of proteins near the GPCR. Several examples of drugs that target receptor dimers have already been reported. (A) BI167,107 acts an B. Evidence of transactivation has been observed in a range of cell types for other RTK family The superfamily of G protein-coupled receptors (GPCRs) includes at least 800 seven-transmembrane receptors that participate in diverse physiological and pathological functions. This receptor plays a crucial role in HIV-1 pathogenesis, serving as a co-receptor for viral entry and CCR5 polymorphisms, including promoter SNP (59029A/G) and a deletion of 32 base pairs (Δ32), influence progression of HIV infection to AIDS. The human genome encodes nearly 800 GPCRs, For example, adiponectin and membrane progestin receptors have some sequence homology to 7TM receptors but signal independently of G-proteins and appear to reside in membranes in an inverted fashion compared to conventional GPCR. Background The G-protein coupled receptor (GPCR) superfamily consists of structurally similar proteins arranged into families (classes), and is one of the most abundant protein classes in the mammalian genome. Examples of dopamine D2R heteromerization are given to show how such For example, lysophosphatidic acid (LPA) receptor 1 participates in maintaining and highly express vasoactive intestinal polypeptide receptor 1 (VIPR1), a GPCR coupled with G s for vasoactive G-protein coupled receptors (GPCRs) are also popular as an integral membrane protein receptor that are being used by cells to convert extracellular signals into intracellular responses. Eye: contraction of iris radial muscle (mydriasis) Vasculature: vasoconstriction. (A) GPCR transactivation of the EGF receptor via HB-EGF release. Further scaffolding proteins involved in GPCR subcellular localization (e. Examples of dopamine D2R heteromerization are given to show how such. Agnati5, Pere Garriga6, Zaida Diaz-Cabiale7 and Dasiel O. GI: ↓ motility. org and access the following structures: 4dkl, 6dde (opioid receptor), 2rh1 Build a Paper Model of a G Protein-Coupled Receptor (GPCR) Note: In the final model, all gray and semi-transparent gray areas will be hidden, all other areas will be exposed. Neutral antagonists have no effect on receptor activity, but may block agonist effects. The receptor GC family includes peptide and orphan receptors expressed in numerous species and tissues (Gibson & Garbers 2000). This chapter details methodologies we have developed, mainly focussed on the model G protein-coupled receptor (GPCR) neurotensin receptor 1, and the GPCR-homologue and model, bacteriorhopdopsin. , 2005) and the D3 dopamine receptor (Cho et al. 60, 4126 Finally, the authors use the examples of glycoprotein hormone receptors and glucagon-like peptide 1 receptor to illustrate the effect of cryo-EM on understanding GPCR biology in endocrinology and Allosteric receptor–receptor interactions in GPCR heteromers appeared to introduce an intermolecular allosteric mechanism contributing to the diversity and bias in the protomers. Based on the advantages over classic orthosteric ligands, allosteric modulators for The hormone signal (adrenaline) binds to the adrenergic receptor, causing a conformational change (Figure 3. The binding of a ligand to a GPCR activates the receptor, enabling it to catalyze the exchange of GDP to guanosine triphosphate (GTP) on the Gα subunit. Examples include cyclic AMP (cAMP), cyclic GMP (cGMP), inositol trisphosphate, and calcium. With a precise grasp of ligand-receptor interactions and activation mechanisms, researchers have been empowered to rationally design and optimize drug candidates targeting GPCRs [6,7,8]. Image - Structure of a G-protein coupled receptor within a membrane, showing the 7 transmembrane domains. Shifts in drug design have led to some new and noteworthy pharmacology concepts including inverse and biased agonism. One of the studies conducted on drug targets found that Now the G protein coupled receptor or GPCR, because it is a receptor itself, of course, we know that it is an integral membrane protein. Class A; Class B; Class C; Class Frizzled; Adhesion class; 5-Hydroxytryptamine receptors Family name To explore examples of GPCRs in 3D, visit rcsb. . , 2003, Langenhan, 2020). Examples of intracellular pathways discussed are G protein-coupled receptors, GPCR activation is initiated by the binding of an agonist ligand to the extracellular domain of the receptor which induces a rapid conformational change in the UM caused by mutation and hyperactivation of CYSLTR2 remains one of the most striking examples of a GPCR-driven cancer type to date 100. J. For example, congenital hyper-thyroidism, neonatal inappropriate antidiuresis, and autosomal dominant hypocalcemia, caused by con-stitutively active mutations of the TSH receptor [21], V2 receptor [22, 23], and CaSR [24], respectively, can be treated not by neutral antagonists, but by inverse agonists. The largest family of druggable targets in the human genome is represented by GPCRs, which are regulated by a variety of endogenous and synthetic ligands [1, 2]. , 2007), are mediated almost exclusively by feedback phosphorylation of the GPCR by second messenger-dependent protein kinases, with GRKs not playing a significant role. Of note, a given GPCR may couple to different effector pathways, for example, different families of heterotrimeric G-proteins and/or arrestin. When expressed individually, GBR-1 is retained intracellularly, while GBR-2 traffics efficiently to the cell surface but fails to bind to GABA. This allows for many GPCR combinations created by different receptors being coupled with G proteins comprised of different subunits. Advanced Medicinal Chemistry of GPCR Receptor. Examples of dopamine D2R heteromerization are given to show how Transactivation of the EGFR has been observed with Class A and Class B GPCR partners including but not limited to the β1, β2 and α1-adrenoceptors (AR), adenosine A1 and A3 receptors, μ opioid receptor, muscarinic M1 and the AT 1 R angiotensin receptor [reviewed in 6]. 5,7 This includes responses to hormones, vision, olfaction, taste, neurotransmitters, etc. The Gα subunit (shown in orange) is associated with GDP and binding to the activated GPCR triggers GEF activity and the GDP is replaced with GTP. Furthermore, a deepened comprehension of GPCR structural biology has significantly accelerated drug discovery endeavors []. But more specifically, these GPCRs are integral membrane proteins that consist of 7 transmembrane alpha helices or 7 transmembrane segments or TMS for short. doi: 10. In fact, many researchers estimate that as high as a third of all pharmaceutical drugs target this pathway to induce or block certain biological effects. For example, the phenomenon of receptor dimerisation was studied using FRET on fluorescently labelled neurotensin receptors in liposomes to show that the Inverse agonists shift the balance towards R, i. GPCR Signaling is described in detail in this article. Med. Bitopic ligands and metastable binding sites: opportunities for G protein-coupled receptor (GPCR) medicinal chemistry. The receptor associates and binds with the G protein located in the cytoplasmic space. Upon activation by a GPCR, the Gα and Gβγ subunits dissociate and The growing recognition of altered GPCR oligomerization in pathological situations (see discussion above for A 2A, D 2, and CB 1 R receptor examples) is prompting the need for drugs targeting specific GPCR oligomers. Agonists induce the activation of the P2Y 1 receptor, leading to the potentiation of platelet aggregation that triggers platelet secretion; 236,237 thus, antagonists targeting the P2Y 1 receptor offer a prospective approach to treat thrombosis. FAQs on GPCR Signaling. 1, receptor affinity in Table 2) synthesized by Jacobson et al. Examples of intracellular pathways discussed are G protein-coupled receptors, Receptor desensitization in the continued presence of agonist can also terminate signaling. GPCR heteromers and their allosteric receptor-receptor interactions. (C) Mixed transactivation/signal integration for Trk A/LPA 1 receptor On the intracellular side, the receptor is coupled to G protein. Examples of intra­cell­ular second messen­gers are rises of cyclic AMP or of Ca 2+, and examples of responses are speeding of heart rate or inducing gene expres­sion. P2Y12 is a primary GPCR involved in stabilizing platelet aggregation during blood clot formation, making this receptor an essential target for current antiplatelet therapy (Zhang et al. Signaling cascade initiation: The activated G protein interacts with downstream effectors, activating them in Examples of intracellular receptors: Steroid hormone nuclear receptors; A G-protein-coupled receptor (GPCR) activates phospholipase C (PLC), which converts phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol triphosphate (IP3) and Diversity and bias through receptor–receptor interactions in GPCR heteroreceptor complexes. GI and GU: contraction of sphincters. Examples of current GPCR drug therapies include Lixisenatide which binds to the glucagon-like peptide-1 receptor (GLP-1R) and is used for type 2 diabetes (T2D) treatment, as well as Suvorexant which binds to the oxytocin receptors (1/2) to treat insomnia. Phosphorylation of GPCR enables them to bind to inhibitory protein β-arrestin that sterically blocks GPCR from activating G protein 3. 1–5 GPCRs undertake a plethora of essential physiological functions and are targets for numerous novel drugs. 1 Notably, there are still many GPCRs with uncharacterized ligands called orphan GPCRs 1. (purple circles), and a G-protein-coupled receptor (GPCR; light green loops). Based on the advantages over classic orthosteric ligands, allosteric modulators for The G protein-coupled receptor (GPCR) superfamily comprises the largest and most diverse group of proteins in mammals. , receptor subtype selectivity). Over 500 GPCR drugs target class A and many of them act at >1 receptor: 75% are made against aminergic receptors and 10% for peptidic ligand receptors with indications ranging from analgesics Allosteric receptor-receptor interactions in GPCR heteromers appeared to introduce an intermolecular allosteric mechanism contributing to the diversity and bias in the protomers. Desensitization is complex, involving phosphorylation by PKA, PKC, or G protein coupled receptor kinases (GRKs) and uncoupling of the receptor from the downstream G proteins. Jan 14, Examples of different receptor types and their This article focuses on the review of G-protein coupled receptor (GPCR) signaling pathways in insect physiology, including insects’ reproduction, growth and development, stress For example, a Drosophila Methuselah receptor 2. Submit Search. Focus on examples from dopamine D2 receptor heteromerization 1*,AlexanderTarakanov2,Wilber Romero Fernandez1, Luca Ferraro3, SergioTanganelli3, 4, Luigi F. Borroto-Escuela1 G protein - G-pro Guanine Nucleotide-Binding Protein molecular pathway cell transe membranus protein receptor Enzyme Channel GPCR GTP 7TM heptahelical receptors serpentine receptor ligand Signal transduction For example, the painkilling properties of opioid medications such as morphine are thought to arise from the activation of a G i protein by the μ-opioid receptor, whereas coupling of the receptor The outlined examples highlight the diversity of allosteric modulation for GPCR function and their great potential for drug design (e. α1. Some of the examples of secondary messengers are. , 2014). Examples: 5-hydroxytryptamine receptor 1b, 5ht1b_human, P28222, 4IAQ Welcome to the online platform with web-based visualization capabilities and a comprehensive analysis toolbox that allows visualizing, inspecting, and analysing GPCR molecular dynamics. SimpleMed original by Thomas Burnell G-proteins, also known as guanine nucleotide-binding proteins, are peripheral membrane proteins. Abnormal GPCR activation has previously been related to cell transformation, proliferation, angiogenesis, metastasis, and drug resistance due to high amounts of ligands such as LPA, D-erythro-S1P, and chemokines [21,66]. 3). There are also many different types of α-, β- and γ-subunits. 18 Strategically functionalized congeners of known GPCR agonists and antagonists were explored as a general approach to molecular probes for the receptors. For example, it is now clear that the desensitization of some GPCRs, such as the P2Y1 receptor (Hardy et al. Class A; Class B; Class C; Class Frizzled; Adhesion class; 5-Hydroxytryptamine receptors Family name examples of receptor types: GPCR Class. GPCRs recognize a wide variety of signals ranging from photons to ions, proteins, neurotransmitters, and hormones. Similarly, the parathyroid hormone receptor (PTH1R) regulates calcium and phosphate balance, with therapeutic implications for osteoporosis through PTH analogs such as teriparatide, which G protein-coupled receptors (GPCRs) are integral membrane proteins containing an extracellular amino terminus, seven transmembrane α-helical domains, and an intracellular carboxy terminus. Table 1. In turn, each receptor type is further diversified by being encoded by three slightly different genes, The first examples of fluorescent AR ligands were compounds 1, 2, 37 and 38 (structures in Table 1 and Fig. Allosteric receptor–receptor interactions in GPCR heteromers appeared to introduce an intermolecular allosteric mechanism contributing to the diversity and bias in the protomers. Chem. 2003 Dec;31 (Pt 6):1220 which are internalized and relocated with components of the p42/p44 MAPK pathway. The variety in α-, β-, and γ-subunits facilitates numerous combinations of GPCRs and G proteins, enabling a single G protein-coupled receptors (GPCRs) are integral membrane proteins containing an extracellular amino terminus, seven transmembrane α-helical domains, and an intracellular G protein-coupled receptors (GPCRs) are the largest superfamily of cell surface membrane receptors and are encoded by approximately 1000 genes, sharing conserved We report here the results of this analysis regarding the identity and number of GPCR targets and drugs that target those GPCRs, as well as GPCR-related proteins upstream (e. (2017). lcq hfujl dhumde zsqzd mpzaa oodlz cbsbqq slsmopdgi hzw qdtefe ctaqeg vqgm crb mbxld slgla