Dataset Information

Towards Probing Conformational States of Y2 Receptor Using Hyperpolarized ¹²⁹Xe NMR.

ABSTRACT: G protein-coupled receptors can adopt many different conformational states, each of them exhibiting different restraints towards downstream signaling pathways. One promising strategy to identify and quantify this conformational landscape is to introduce a cysteine at a receptor site sensitive to different states and label this cysteine with a probe for detection. Here, the application of NMR of hyperpolarized ¹²⁹Xe for the detection of the conformational states of human neuropeptide Y2 receptor is introduced. The xenon trapping cage molecule cryptophane-A attached to a cysteine in extracellular loop 2 of the receptor facilitates chemical exchange saturation transfer experiments without and in the presence of native ligand neuropeptide Y. High-quality spectra indicative of structural states of the receptor-cage conjugate were obtained. Specifically, five signals could be assigned to the conjugate in the apo form. After the addition of NPY, one additional signal and subtle modifications in the persisting signals could be detected. The correlation of the spectroscopic signals and structural states was achieved with molecular dynamics simulations, suggesting frequent contact between the xenon trapping cage and the receptor surface but a preferred interaction with the bound ligand.

SUBMITTER: Schmidt P

PROVIDER: S-EPMC9919357 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Towards Probing Conformational States of Y2 Receptor Using Hyperpolarized <sup>129</sup>Xe NMR.

Schmidt Peter P Vogel Alexander A Schwarze Benedikt B Seufert Florian F Licha Kai K Wycisk Virginia V Kilian Wolfgang W Hildebrand Peter W PW Mitschang Lorenz L

Molecules (Basel, Switzerland) 20230202 3

G protein-coupled receptors can adopt many different conformational states, each of them exhibiting different restraints towards downstream signaling pathways. One promising strategy to identify and quantify this conformational landscape is to introduce a cysteine at a receptor site sensitive to different states and label this cysteine with a probe for detection. Here, the application of NMR of hyperpolarized <sup>129</sup>Xe for the detection of the conformational states of human neuropeptide Y ...[more]

PMID: 36771089

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Project description:BackgroundMRI of hyperpolarized 129 Xenon (HP 129 Xe) is increasingly utilized for investigating pulmonary function. The solubility of HP 129 Xe in lung tissue, blood plasma (Barrier), and red blood cells (RBC), with unique chemical shifts, enables spectroscopic imaging of potential imaging biomarkers of gas exchange and microstructural pulmonary physiology.PurposeTo quantify global average and regional repeatability of Barrier:gas, RBC:gas, and RBC:Barrier ratios derived from dissolved-phase 129 Xe imaging and their dependence on intervisit changes in lung inflation volume.Study typeProspective.PopulationFourteen healthy volunteers. One subject was unable to complete the study resulting in 13 subjects for analysis (eight female, five male, ages 24-69, 53.8 ± 13.9).Field strength1.5T.AssessmentSubjects were imaged using a 3D radial 1-point Dixon method to separate Barrier and RBC component signals, at two different timepoints, with ~1 month between visits. RBC:Gas, Barrier:Gas, and RBC:Barrier measures were compared across time and with pulmonary function tests (PFTs).Statistical testsRepeatablilty was quantified using Bland-Altman plots, coefficient of repeatability, coefficient of variation (CV), and intraclass correlation coefficients (ICCs). Dependence of imaging measures on PFTs and lung volume was evaluated using Spearman and Pearson correlation coefficients, respectively. Statistical significance was determined by F-test for intraclass correlations, and t-test for Spearman correlations and regression.ResultsMean RBC:Gas, Barrier:Gas, and RBC:Barrier had CVs of 19.2%, 20.0%, and 11.5%, respectively, and had significant ICCs, equal to 0.78, 0.79, and 0.92, respectively. Intervisit differences in RBC:Barrier were significantly correlated with intervisit differences in DLCO (r = 0.93, P = 0.007). Significant correlations with intervisit lung volume differences and intervisit differences in mean RBC:Gas (r = -0.73, P = 0.005) and Barrier:Gas (r = -0.69, P = 0.009) were found.Data conclusionThree commonly used 129 Xe MRI-based measures of gas-exchange show good repeatability, particularly the Barrier:RBC ratio, which did not depend on lung inflation volume and was strongly associated with intervisit changes in DLCO .Level of evidence1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;50:1182-1190.

Project description:Introduction: The ideal contrast agents for ventilation SPECT and MRI are Technegas and 129Xe gas, respectively. Despite increasing interest in the clinical utility of ventilation imaging, these modalities have not been directly compared. Therefore, our objective was to compare the ventilation defect percent (VDP) assessed by Technegas SPECT and hyperpolarized 129Xe MRI in patients scheduled to undergo lung cancer resection with and without pre-existing obstructive lung disease. Methods: Forty-one adults scheduled to undergo lung cancer resection performed same-day Technegas SPECT, hyperpolarized 129Xe MRI, spirometry, and diffusing capacity of the lung for carbon monoxide (DLCO). Ventilation abnormalities were quantified as the VDP using two different methods: adaptive thresholding (VDPT) and k-means clustering (VDPK). Correlation and agreement between VDP quantified by Technegas SPECT and 129Xe MRI were determined by Spearman correlation and Bland-Altman analysis, respectively. Results: VDP measured by Technegas SPECT and 129Xe MRI were correlated (VDPT: r = 0.48, p = 0.001; VDPK: r = 0.63, p < 0.0001). A 2.0% and 1.6% bias towards higher Technegas SPECT VDP was measured using the adaptive threshold method (VDPT: 23.0% ± 14.0% vs. 21.0% ± 5.2%, p = 0.81) and k-means method (VDPK: 9.4% ± 9.4% vs. 7.8% ± 10.0%, p = 0.02), respectively. For both modalities, higher VDP was correlated with lower FEV1/FVC (SPECT VDPT: r = -0.38, p = 0.01; MRI VDPK: r = -0.46, p = 0.002) and DLCO (SPECT VDPT: r = -0.61, p < 0.0001; MRI VDPK: r = -0.68, p < 0.0001). Subgroup analysis revealed that VDP measured by both modalities was significantly higher for participants with COPD (n = 13) than those with asthma (n = 6; SPECT VDPT: p = 0.007, MRI VDPK: p = 0.006) and those with no history of obstructive lung disease (n = 21; SPECT VDPT: p = 0.0003, MRI VDPK: p = 0.0003). Discussion: The burden of ventilation defects quantified by Technegas SPECT and 129Xe MRI VDP was correlated and greater in participants with COPD when compared to those without. Our observations indicate that, despite substantial differences between the imaging modalities, quantitative assessment of ventilation defects by Technegas SPECT and 129Xe MRI is comparable.

Dataset Information

Towards Probing Conformational States of Y2 Receptor Using Hyperpolarized ¹²⁹Xe NMR.

Publications

Towards Probing Conformational States of Y2 Receptor Using Hyperpolarized <sup>129</sup>Xe NMR.

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Dataset Information

Towards Probing Conformational States of Y2 Receptor Using Hyperpolarized 129Xe NMR.

Publications

Towards Probing Conformational States of Y2 Receptor Using Hyperpolarized <sup>129</sup>Xe NMR.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Towards Probing Conformational States of Y2 Receptor Using Hyperpolarized ¹²⁹Xe NMR.