Search Results
521 items found for "Jespers W"
- N-Acyl Amides from Neisseria meningitidis and Their Role in Sphingosine Receptor Signaling
Here, we heterologously expressed an N-acyltransferase encoded in the obligate human pathogen N. meningitidis During this process, we also characterized two mammalian N-acyl amides derived from the bovine medium
- Function and structure of bradykinin receptor 2 for drug discovery
determined structures of B2R have provided molecular insights into the functions and regulation of B2R, which In this review, we summarize the structure and function of B2R in relation to drug discovery and discuss
- Use of CRISPR/Cas9-edited HEK293 cells reveals that both conventional and novel protein kinase C...
In this study, we generated and characterized human embryonic kidney 293A (HEK293A) cell lines devoid Nonetheless, we determined that mGlu5a internalization was not altered upon the loss of cPKCs or nPKCs cells, and a receptor containing a mutated putative adaptor protein complex 2 (AP-2) interaction motif, we Moreover, since pharmacological tools to study PKC isozymes generally lack specificity and/or potency, we
- Single-molecule counting applied to the study of GPCR oligomerization
While early evidence for the role of oligomerization in receptor signaling came from ensemble biochemical Here, we review recent developments in single-molecule counting with a focus on photobleaching step counting
- Network pharmacological investigation into the mechanism of Kaixinsan powder for the treatment of...
depression "Kaixinsan powder (KXS), a classic prescription of traditional Chinese Medicine (TCM), is widely
- Activation of GPR183 by 7 α,25-Dihydroxycholesterol Induces Behavioral Hypersensitivity through...
Here, we show that 7α,25-OHC-induced behavioral hypersensitivity is Gα i dependent, but not β-arrestin In support, we found that the development of 7α,25-OHC/GPR183-induced mechano-allodynia was associated SIGNIFICANCE STATEMENT: Using a multi-disciplinary approach, we have characterized the molecular mechanisms We found that 7α,25-OHC-induced allodynia is dependent on MAPK and NF-κB signaling pathways and results
- Regulation of pulmonary surfactant by the adhesion GPCR GPR116/ADGRF5 requires a tethered agonist...
We set out to investigate the physiological importance of autocatalytic cleavage upstream of the agonistic To examine this hypothesis, we characterized tethered agonist-mediated activation of GPR116 in vitro Using site-directed mutagenesis and species-swapping approaches, we identified key conserved amino acids We further highlight residues in transmembrane 7 (TM7) that mediate stronger signaling in mouse versus
- Specific Functions of Melanocortin 3 Receptor (MC3R)
In addition to its function about weight gain and appetite control mechanisms of MC3R, recent studies showed that MC3R controls growth, puberty, and circadian rhythms as well. In this review paper, we aimed to point out the importance of the MC3R regulations in three main concepts : 1) its impact on weight and appetite control, 2) the control of growth, puberty, and circadian rhythm
- Enhanced membrane binding of oncogenic G protein αqQ209L confers resistance to inhibitor YM-254890
YM-254890 (YM) can inhibit signaling by both GPCR-activated wild type αq and GPCR-independent αqQ209L Although YM inhibits wild type αq by binding to αq-GDP and preventing GDP/GTP exchange, the mechanism Here, we show that YM promotes a subcellular redistribution of αqQ209L from the plasma membrane (PM) test if this loss of PM localization could contribute to the mechanism of inhibition of αqQ209L by YM, we GPCR-dependent signaling by PM-restricted wild type αq is strongly inhibited by YM, demonstrating that
- Viral G Protein-Coupled Receptors Encoded by β- and γ-Herpesviruses
These include receptors from human cytomegalovirus, which encodes four vGPCRs: US27, US28, UL33, and We discuss ligand binding, signaling, and structures of the vGPCRs in light of robust differences from Finally, we briefly discuss the therapeutic targeting of vGPCRs as future treatment of acute and chronic
- Adenosine receptor signalling in Alzheimer's disease
Targeting these receptors preclinically can mitigate pathogenic β-amyloid and tau neurotoxicity whilst In this review, we provide an accessible summary of the literature on Alzheimer's disease and the therapeutic Although there are no available medicines targeting these receptors approved for treating dementia, we provide insights into some novel strategies, including allosterism and the targeting of oligomers, which
- Focusing on the role of secretin/adhesion (Class B) G protein-coupled receptors in placental...
preeclampsia "Preeclampsia, a clinical syndrome mainly characterized by hypertension and proteinuria, with a worldwide protein-coupled receptors in the regulation of cardiovascular system function and the drug target exploration, we
- Membrane Lipids Are an Integral Part of Transmembrane Allosteric Sites in GPCRs: A Case Study of...
Using classical and enhanced molecular dynamics simulations, we show that membrane lipids are critical
- Genome-scale CRISPR screening reveals that C3aR signaling is critical for rapid capture of fungi...
capture of fungi by macrophages "The fungal pathogen Histoplasma capsulatum (Hc) invades, replicates within To interrogate the molecular mechanisms underlying this interaction, we conducted a host-directed CRISPR-Cas9 We demonstrated that whereas C3aR is dispensable for macrophage phagocytosis of bacteria and latex beads We showed that C3aR localizes to the early phagosome during Hc infection where it coordinates the formation We also showed that the EMC promotes surface expression of C3aR, likely explaining its identification
- Keratinocyte-derived defensins activate neutrophil-specific receptors Mrgpra2a/b to prevent skin...
Here, we discovered that the epithelial-cell-derived antimicrobial peptides defensins activated orphan We generated mutant mouse lines lacking the entire Defensin (Def) gene cluster in keratinocytes or Mrgpra2a Defensins and Mrgpra2 were critical for combating S. aureus infections and the formation of neutrophil Activation of Mrgpra2 by defensin triggered neutrophil release of IL-1β and CXCL2 which are vital for
- Structure-Based Discovery of Negative Allosteric Modulators of the Metabotropic Glutamate Receptor 5
In this work, molecular docking screens for allosteric modulators targeting the metabotropic glutamate receptor 5 (mGlu5) were performed. Among the top-ranked compounds, 59 fragments and 59 lead-like compounds were selected for experimental Of these, four fragment- and seven lead-like compounds were confirmed to bind to the allosteric site The four compounds with the highest affinities were demonstrated to be negative allosteric modulators
- GPR15 expressed in T lymphocytes from RA patients is involved in leukocyte chemotaxis to the...
chemotaxis to the synovium "The rheumatoid arthritis (RA) inflammatory process occurs in the joints where We evaluated the expression of GPR15 and GPR15L in blood and synovial tissue samples from RA patients , as well as to perform a functional migration assay in response to GPR15L. Samples of synovial fluid and peripheral blood were analyzed for CD45+CD3+CD4+GPR15+ and CD45+CD3+CD8 Statistical analysis included Kruskal-Wallis test, T-test, or Mann-Whitney U test, according to data
- Successful prednisolone or calcimimetic treatment of acquired hypocalciuric hypercalcemia caused...
This emphasizes the importance of the Gi/o (pertussis toxin-sensitive G proteins, whose βγ subunits activate We here describe 3 patients with symptomatic AHH who shared characteristics with the 2 cases we previously the presence of CaSR autoantibodies that operated as biased allosteric modulators of CaSR, and (g) were commonalities may provide new insights into the phenotype and characteristics of AHH and the mechanisms by which
- Dual loss of regulator of G protein signaling 2 and 5 exacerbates ventricular myocyte arrhythmias...
Whether RGS2 and 5 redundantly control G protein signaling to maintain cardiovascular homeostasis is Here we examined how the dual absence of RGS2 and 5 (Rgs2/5 dbKO) affects blood pressure and cardiac
- Case Report of a Juvenile Patient with Autism Spectrum Disorder with a Novel Combination of Copy...
Spectrum Disorder with a Novel Combination of Copy Number Variants in ADGRL3 (LPHN3) and Two Pseudogenes "We Using array-based comparative genomic hybridization (array-CGH), we identified two CNVs, both triplex
- Identification of A2BAR as a potential target in colorectal cancer using novel fluorescent GPCR...
novel fluorescent GPCR ligands "G-protein coupled receptors (GPCRs) have been largely targeted in a wide Here, using colorectal cancer (CRC) as a model, we explored the gene expression of a panel of GPCRs in We selected the adenosine receptor 2B (A2BAR), specifically expressed in cancer cell lines compared with As well, fluorescent ligands were effective at monitoring real-time A2BAR receptor labeling using live-imaging Finally, we validated A2BAR as a potential pharmacological tool in CRC, using selective antagonists,
- Increased Anxiety-like Behaviors in Adgra1-/- Male But Not Female Mice are Attributable to...
We found that Adgra1 is highly and exclusively expressed in the brain, suggesting that Adgra1 may be To this end, we comprehensively analyzed the potential role of ADGRA1 in the neurobehaviors of mice by comparing Adgra1-/- and their wild-type (wt) littermates. Finally, we found that PI3K/AKT/GSK-3β and MEK/ERK in amygdalae of Adgra1-deficient male mice were aberrantly activated when compared to wt male mice.
- Intermolecular Interactions in G Protein-Coupled Receptor Allosteric Sites at the Membrane Interface
In this work, we analyze interactions in the allosteric sites of the PAR2, C5aR1, and GCGR receptors We show that besides classical hydrogen bonds, weak polar interactions such as O-HC, O-Br, and long-range The availability of polar atoms for interactions in such cavities can be assessed by water molecules Although ligand-lipid interactions are weak, lipid tails play a role in ligand binding pose stability library enriched by weak donor groups for ligand search in such sites."
- Structural basis of adhesion GPCR GPR110 activation by stalk peptide and G-proteins coupling
Here, we report the cryo-electron microscopy structures of GPR110 (ADGRF1), a member of aGPCR, in complex This is also where Gq/Gs bind the receptor through both hydrophobic and polar interaction, while Gi/G12 We further provide physiological evidence of GPR110 activation via stalk peptide.
- Endogenous ligand recognition and structural transition of a human PTH receptor
two ligands have distinct signaling and physiological properties: PTH evokes prolonged Gs activation, whereas Here, we report cryoelectron microscopic structures of six forms of the human PTH1R-Gs complex in the
- Discovery and In Vivo Evaluation of ACT-660602: A Potent and Selective Antagonist of the Chemokine..
Starting from a high-throughput screening hit, we describe the iterative optimization of a chemical series significantly reduced recruitment of the CXCR3+ CD8+ T cell in the bronchoalveolar lavage compartment when
- Structural view of G protein-coupled receptor signaling in the retinal rod outer segment
We summarize recent discoveries that have advanced our understanding of rod outer segment (ROS) morphology We have combined recently published cryo-electron tomography (cryo-ET) data on the ROS with structural knowledge on individual proteins to define the precise spatial limitations under which phototransduction guanylate cyclases (GCs) in maintaining the spacing between ROS discs, suggesting a plausible mechanism by which
- GPCR Agonist-to-Antagonist Conversion: Enabling the Design of Nucleoside Functional Switches for...
Herein, we demonstrate that a thiophene modification at the C8 position in the common adenine scaffold We synthesized and characterized a novel A2AAR antagonist, 2 (LJ-4517), with Ki = 18.3 nM. X-ray crystallographic structures of 2 in complex with two thermostabilized A2AAR constructs were solved In contrast to A2AAR agonists, which simultaneously interact with both Ser2777.42 and His2787.43, 2 only transiently contacts His2787.43, which can be direct or water-mediated.