• Exploring the Molecular Therapeutic Mechanisms of Gemcitabine through Quantitative Proteomics

    分类: 药物科学 >> 生物化学 提交时间: 2024-06-14

    摘要: Gemcitabine (GEM) is a potent chemotherapeutic agent widely employed in the treatment of various cancers, notably pancreatic cancer. Despite its clinical success, challenges related to GEM resistance and toxicity persist. Therefore, there is a pressing need for a deeper understanding of its intracellular mechanisms and potential targets. In this study, we utilized quantitative proteomics and thermal proteome profiling (TPP) to elucidate the effects of GEM. Our proteomic analysis revealed that GEM primarily affected DNA synthesis, leading to the upregulation of cell cycle and DNA replication proteins. Additionally, enrichment analysis highlighted the activation of the p53 pathway, shedding light on GEM-induced apoptosis mechanisms. Notably, we observed the upregulation S-phase kinase-associated protein 2 (SKP2), a cell cycle and chemoresistance regulator, in response to GEM treatment. Combining SKP2 inhibition with GEM showed synergistic effects in both cellular and animal models, suggesting SKP2 as a potential target for enhancing GEM sensitivity and overcoming chemoresistance. Furthermore, through TPP, we explored potential binding targets of GEM, which implies GEM’s broad anticancer effects. Together, these findings provide valuable insights into GEM’s molecular mechanisms and offer potential targets for improving treatment efficacy. This research holds the promise of advancing personalized treatment strategies and opening avenues for novel combination therapies to enhance outcomes in pancreatic cancer.

  • Muon energy reconstruction in the high-energy neutrino observations

    分类: 天文学 >> 天文仪器与技术 提交时间: 2024-06-06 合作期刊: 《天文技术与仪器(英文)》

    摘要:The reconstruction of muon energies is crucial for the data analysis of neutrino experiments using large water Cherenkov detectors, but the resolution for muon energy reconstruction using traditional methods is poor. Here, we propose a revised approach to remove noisy optical modules along the track produced by the propagation of muons through water. The number of photons on the optical modules is first corrected by the attenuation properties of light in water. Then the difference in time between the observed optical modules and the expected ones is determined based on the geometry of the triggered optical modules. Finally, the standard of correction is measured by the ratio of photon number before and after correction. Optical modules selection conditions were optimized according to these parameters, with most noisy optical modules successfully removed, improving the resolution of muon energy reconstruction.

  • A high-contrast imaging coronagraph for segmented-mirror large aperture telescopes using a spatial light modulator

    分类: 天文学 >> 天文仪器与技术 提交时间: 2024-06-06 合作期刊: 《天文技术与仪器(英文)》

    摘要:The primary mirrors of current and future large telescopes always employ a segmented mirror configuration. The small but non-negligible gaps between neighboring segments cause additional diffraction, which restricts the performance of high-contrast coronagraph. To solve this problem, we propose a coronagraph system based on a single liquid crystal spatial light modulator (SLM). This spatial light modulator is used for amplitude apodization, and its feasibility and potential performance are demonstrated using a laboratory setup using the stochastic parallel gradient descent (SPGD) algorithm to control the spatial light modulator, which is based on point spread function (PSF) sensing and evaluation and optimized for maximum contrast in the discovery working area as a merit function. The system delivers a contrast in the order of 10−6, and shows excellent potential to be used in current and future large aperture telescopes, both on the ground and in space.

  • Fuzzy Proportional Integral Derivative control of a voice coil actuator system for adaptive deformable mirrors

    分类: 天文学 >> 天文仪器与技术 提交时间: 2024-06-06 合作期刊: 《天文技术与仪器(英文)》

    摘要:Research on adaptive deformable mirror technology for voice coil actuators (VCAs) is an important trend in the development of large ground-based telescopes. A voice coil adaptive deformable mirror contains a large number of actuators, and there are problems with structural coupling and large temperature increases in their internal coils. Additionally, parameters of the traditional proportional integral derivative (PID) control cannot be adjusted in real-time to adapt to system changes. These problems can be addressed by introducing fuzzy control methods. A table lookup method is adopted to replace real-time calculations of the regular fuzzy controller during the control process, and a prototype platform has been established to verify the effectiveness and robustness of this process. Experimental tests compare the control performance of traditional and fuzzy proportional integral derivative (Fuzzy-PID) controllers, showing that, in system step response tests, the fuzzy control system reduces rise time by 20.25%, decreases overshoot by 78.24%, and shortens settling time by 67.59%. In disturbance rejection experiments, fuzzy control achieves a 46.09% reduction in the maximum deviation, indicating stronger robustness. The Fuzzy-PID controller, based on table lookup, outperforms the standard controller significantly, showing excellent potential for enhancing the dynamic performance and disturbance rejection capability of the voice coil motor actuator system.

  • Cone-beam computed tomography noise reduction method based on U-Net with convolutional block attention module in proton therapy

    分类: 核科学技术 >> 辐射物理与技术 提交时间: 2024-05-30

    摘要: Cone-beam computed tomography (CBCT) is mostly used for position verification during the treatment pro#2;cess. However, severe image artifacts in CBCT hinder its direct use in dose calculation and adaptive radiationtherapy re-planning for proton therapy. In this study, an improved U-Net neural network named CBAM-U-Netwas proposed for CBCT noise reduction in proton therapy, which is a CBCT denoised U-Net network with con#2;volutional block attention modules. The datasets contained 20 groups of head and neck images. The CT imageswere registered to CBCT images as ground truth. The original CBCT denoised U-Net network, sCTU-Net, wastrained for model performance comparison. The synthetic CT(SCT) images generated by CBAM-U-Net and theoriginal sCTU-Net are called CBAM-SCT and U-Net-SCT images, respectively. The HU accuracies of the CT,CBCT, and SCT images were compared using four metrics: mean absolute error (MAE), root mean square error(RMSE), peak signal-to-noise ratio (PSNR), and structure similarity index measure (SSIM). The mean values ofthe MAE, RMSE, PSNR, and SSIM of CBAM-SCT images were 23.80 HU, 64.63 HU, 52.27 dB, and 0.9919,respectively, which were superior to those of the U-Net-SCT images. To evaluate dosimetric accuracy, the rangeaccuracy was compared for a single-energy proton beam. The γ-index pass rates of a 4 cm × 4 cm scannedfield and simple plan were calculated to compare the effects of the noise reduction capabilities of the originalU-Net and CBAM-U-Net on the dose calculation results. CBAM-U-Net reduced noise more effectively thansCTU-Net, particularly in high-density tissues. We proposed a CBAM-U-Net model for CBCT noise reductionin proton therapy. Owing to the excellent noise reduction capabilities of CBAM-U-Net, the proposed modelprovided relatively explicit information regarding patient tissues. Moreover, it can be used in dose calculationand adaptive treatment planning in the future.

  • Near-surface wind field characteristics of the desert-oasis transition zone in Dunhuang, China

    分类: 地球科学 >> 大气科学 提交时间: 2024-05-15 合作期刊: 《干旱区科学》

    摘要: The desert-oasis transition zone (DOTZ) serves as a buffer area between the desert and oasis. Understanding its wind field characteristics is of great significance for the prevention and control of aeolian disasters in the oasis. In this study, we used meteorological data during 2013–2019 from the portable meteorological stations at five sites (site A on the edge of the oasis, sites B, C, and D in the DOTZ, and site O in the desert) in Dunhuang, China to analyze the near-surface wind field characteristics and their causes, as well as to reveal the key role of the DOTZ in oasis protection. The results showed that the mean wind speed, frequency of sand-driving wind, and directional variability of wind decreased from west to east within the DOTZ, and wind speed was significantly affected by air temperature. The terrain influenced the prevailing winds in the region, mainly from northeast and southwest. Only some areas adjacent to the oasis were controlled by southeasterly wind. This indicated that the near-surface wind field characteristics of the DOTZ were caused by the combined effects of local terrain and surface hydrothermal difference. At site D, the annual drift potential (DP) was 24.95 vector units (VU), indicating a low wind energy environment, and the resultant drift direction (RDD) showed obvious seasonal differences. Additionally, the DOTZ played an important buffering role between the desert and oasis. Compared with the desert, the mean wind speed in the oasis decreased by 64.98%, and the prevailing wind direction was more concentrated. The results of this study will be useful in interpreting the aeolian activity of the DOTZ in Dunhuang.

  • Efficient and selective removal of Pb(II) from landfill leachate using L-serine-modified polyethylene/polypropylene nonwoven fabric synthesized via radiation grafting technique

    分类: 核科学技术 >> 核科学技术其他学科 提交时间: 2024-05-08

    摘要: In this study, to efficiently remove Pb(II) from aqueous environments, a novel L-serine-modified polyethylene/polypropylene nonwoven fabric sorbent (NWF-serine) was fabricated through the radiation grafting of glycidyl methacrylate and subsequent L-serine modification. The effect of the absorbed dose was investigated in the range of 5–50 kGy. NWF-serine was characterized by Fourier transform infrared spectroscopy, thermogravimetric analysis, and scanning electron microscopy. Batch adsorption tests were conducted to investigate the influences of pH, adsorption time, temperature, initial concentration, and sorbent dosage on the Pb(II) adsorption performance of NWF-serine. The results indicated that Pb(II) adsorption onto NWF-serine was an endothermic process, following the pseudo-second-order kinetic model and Langmuir isotherm model. The saturated adsorption capacity was 198.1 mg/g. NWF-serine exhibited Pb(II) removal rates of 99.8% for aqueous solutions with initial concentrations of 100 mg/L and 82.1% for landfill leachate containing competitive metal ions such as Cd, Cu, Ni, Mn, and Zn. Furthermore, NWF-serine maintained 86% of its Pb(II) uptake after five use cycles. The coordination of the carboxyl and amino groups with Pb(II) was confirmed using X-ray photoelectron spectroscopy and extended X-ray absorption fine structure analysis.

  • A real-time calibration method based on time-to-digital converter for accelerator timing system

    分类: 物理学 >> 核物理学 提交时间: 2024-04-28

    摘要: The high-intensity heavy-ion accelerator facility (HIAF) is a scientific research facility complex composed ofmultiple cascade accelerators of different types, which pose a scheduling problem for devices distributed overa certain range of 2 km, involving over a hundred devices. The White Rabbit (WR), a technology-enhancingGigabit Ethernet, has shown the capability of scheduling distributed timing devices but still faces the challengeof obtaining real-time synchronization calibration parameters with high precision. This study presents a calibra#2;tion system based on a time-to-digital converter implemented on an ARM-based System-on-Chip (SoC). Thesystem consists of four multi-sample delay lines, a bubble-proof encoder, an edge controller for managing datafrom different channels, and a highly effective calibration module that benefits from the SoC architecture. Theperformance was evaluated with an average RMS precision of 5.51 ps by measuring the time intervals from 0to 24000 ps with 120000 data for every test. The design presented in this study refines the calibration precisionof the HIAF timing system. This eliminates the errors caused by manual calibration without efficiency loss andprovides data support for fault diagnosis. It can also be easily tailored or ported to other devices for specificapplications and provides more space for developing timing systems for particle accelerators, such as whiterabbits on HIAF.

  • Decoding homodimerization and antidepressant recognition at the norepinephrine transporter

    分类: 药物科学 >> 结构生物学 提交时间: 2024-04-27

    摘要: The norepinephrine transporter (NET) plays a pivotal role in regulating neurotransmitter balance and is critical for normal physiology and neurobiology. Dysfunction of NET has been implicated in numerous neuropsychiatric diseases including depression, anxiety, attention deficit hyperactivity disorder, and Parkinson’s disease. Here we report cryo-EM structures of NET in apo and substrate-bound forms, as well as complexes with six antidepressants. The structures reveal an unexpected NET dimer interface predominantly mediated by cholesterol and lipid molecules. The substrate norepinephrine is found to bind deep within the central binding pocket, with its amine group interacting with a conserved aspartate. The structures also provide insight into antidepressant recognition, including how subtle differences in binding poses confer selectivity over other monoamine transporters. Together these breakthrough findings significantly advance our understanding of NET regulation and inhibition, providing templates for designing improved antidepressants to treat neuropsychiatric disorders.

  • Solar adaptive optics systems for the New Vacuum Solar Telescope at the Fuxian Lake Solar Observatory

    分类: 天文学 >> 天文仪器与技术 提交时间: 2024-04-18 合作期刊: 《天文技术与仪器(英文)》

    摘要:Adaptive optics (AO) is essential for high-quality ground-based observations with large telescopes because it counters the impact of wavefront aberrations caused by atmospheric turbulence. The new vacuum solar telescope(NVST) is one of the most important high-resolution solar observation instruments in the world. Three sets of solar adaptive optics systems have been developed and installed on this telescope: conventional adaptive optics, ground layer adaptive optics, and multi- conjugate adaptive optics. These have been in operation from 2018 to 2023. This paper details the development and application of solar adaptive optics on the NVST and discusses the newest instrumentation.

  • Superconductivity of Bulk Abnormal Magic-stoichiometric Na3Cl Salt Crystals at Normal Pressure

    分类: 物理学 >> 凝聚态:电子结构、电、磁和光学性质 提交时间: 2024-04-17

    摘要: The identification of new materials with superconducting properties is the pursuit in the realm of superconductivity research. Here, excitedly, we show that the simplest salt daily used can be made a superconductor at normal pressure only by adjusting its stoichiometry of Na and Cl as Na3Cl at normal pressure based on first-principles calculations. This bulk stable abnormal Na-Cl stoichiometric crystal of 3:1, the first ‘magic’ ratio, includes metallic (Na) atoms in the core as well as hybridization of ionic and metallic bonding, facilitating the electron-phonon-coupling for superconductivity with a critical temperature Tc of 0.13 K. The flat bands and van Hove singularities near the Fermi level produce large densities of states, similar to H3S and LaH10, which is beneficial for the emergence of superconductivity. The crystal composed of with abnormal Na-Cl magic stoichiometry is a precisely tunable, purely sodium and chloride-based, three-dimensional bulk superconductor, which is therefore an ideal material for designing and understanding abnormal stoichiometric crystals. The methodology of constructing this bulk abnormal crystal may be general to almost all elements, which could lead to insights into the physics of other conventional superconductors and even high-critical-temperature superconductors.

  • Effects of wind speed, underlying surface, and seed morphological traits on the secondary seed dispersal in the Tengger Desert, China

    分类: 生物学 >> 植物学 提交时间: 2024-04-15 合作期刊: 《干旱区科学》

    摘要: The maintenance of sand-fixing vegetation is important for the stability of artificial sand-fixing systems in which seed dispersal plays a key role. Based on field wind tunnel experiments using 11 common plant species on the southeastern edge of the Tengger Desert, China, we studied the secondary seed dispersal in the fixed and semi-fixed sand dunes as well as in the mobile dunes in order to understand the limitations of vegetation regeneration and the maintenance of its stability. Our results indicated that there were significant variations among the selected 11 plant species in the threshold of wind speed (TWS). The TWS of Caragana korshinskii was the highest among the 11 plant species, whereas that of Echinops gmelinii was the lowest. Seed morphological traits and underlying surface could generally explain the TWS. During the secondary seed dispersal processes, the proportions of seeds that did not disperse (no dispersal) and only dispersed over short distance (short-distance dispersal within the wind tunnel test section) were significantly higher than those of seeds that were buried (including lost seeds) and dispersed over long distance (long-distance dispersal beyond the wind tunnel test section). Compared with other habitats, the mobile dunes were the most difficult places for secondary seed dispersal. Buried seeds were the easiest to be found in the semi-fixed sand dunes, whereas fixed sand dunes were the best sites for seeds that dispersed over long distance. The results of linear mixed models showed that after controlling the dispersal distance, smaller and rounder seeds dispersed farther. Shape index and wind speed were the two significant influencing factors on the burial of seeds. The explanatory power of wind speed, underlying surface, and seed morphological traits on the seeds that did not disperse and dispersed over short distance was far greater than that on the seeds that were buried and dispersed over long distance, implying that the processes and mechanisms of burial and long-distance dispersal are more complex. In summary, most seeds in the study area either did not move, were buried, or dispersed over short distance, promoting local vegetation regeneration.

  • Spatiotemporal variability of rain-on-snow events in the arid region of Northwest China

    分类: 地球科学 >> 大气科学 提交时间: 2024-04-15 合作期刊: 《干旱区科学》

    摘要: Rain-on-snow (ROS) events involve rainfall on snow surfaces, and the occurrence of ROS events can exacerbate water scarcity and ecosystem vulnerability in the arid region of Northwest China (ARNC). In this study, using daily snow depth data and daily meteorological data from 68 meteorological stations provided by the China Meteorological Administration National Meteorological Information Centre, we investigated the spatiotemporal variability of ROS events in the ARNC from 1978 to 2015 and examined the factors affecting these events and possible changes of future ROS events in the ARNC. The results showed that ROS events in the ARNC mainly occurred from October to May of the following year and were largely distributed in the Qilian Mountains, Tianshan Mountains, Ili River Valley, Tacheng Prefecture, and Altay Prefecture, with the Ili River Valley, Tacheng City, and Altay Mountains exhibiting the most occurrences. Based on the intensity of ROS events, the areas with the highest risk of flooding resulting from ROS events in the ARNC were the Tianshan Mountains, Ili River Valley, Tacheng City, and Altay Mountains. The number and intensity of ROS events in the ARNC largely increased from 1978 to 2015, mainly influenced by air temperature and the number of rainfall days. However, due to the snowpack abundance in areas experiencing frequent ROS events in the ARNC, snowpack changes exerted slight impact on ROS events, which is a temporary phenomenon. Furthermore, elevation imposed lesser impact on ROS events in the ARNC than other factors. In the ARNC, the start time of rainfall and the end time of snowpack gradually advanced from the spring of the current year to the winter of the previous year, while the end time of rainfall and the start time of snowpack gradually delayed from autumn to winter. This may lead to more ROS events in winter in the future. These results could provide a sound basis for managing water resources and mitigating related disasters caused by ROS events in the ARNC.

  • Design and Construction of Charged Particle Telescope Array for Study of Exotic Nuclear Clustering Structure

    分类: 物理学 >> 核物理学 提交时间: 2024-03-19

    摘要: The exploration of exotic shapes and properties of atomic nuclei, e.g., α cluster and toroidal shape, is afascinating field in nuclear physics. To study the decay of these nuclei, a novel detector aimed at detectingmultiple alpha-particle events was designed and constructed. The detector comprises two layers of double-sidedsilicon strip detectors (DSSD) and a cesium iodide scintillator array coupled with silicon photomultipliers arrayas light sensors, which has the advantages of their small size, fast response, and large dynamic range. DSSDscouple with cesium iodide crystal arrays are used to distinguish multiple alpha hits. The detector array has acompact and integrated design that can be adapted to different experimental conditions. The detector array wassimulated using Geant4, and the excitation energy spectra of some alpha-clustering nuclei were reconstructedto demonstrate the performance. The simulation results show that the detector array has excellent angularand energy resolutions, enabling effective reconstruction of the nuclear excited state by multiple alpha particleevents. This detector offers a new and powerful tool for nuclear physics experiments and has the potential todiscover interesting physical phenomena related to exotic nuclear structures and their decay mechanisms

  • Feasibility study of the photonuclear reaction cross section of medical radioisotopes using a laser Compton scattering gamma source

    分类: 物理学 >> 核物理学 提交时间: 2024-03-19

    摘要: In recent years, the gap between the supply and demand of medical radioisotopes has increased, necessitating new methods for producing medical radioisotopes. Photonuclear reactions based on gamma sources have unique advantages in terms of producing high specific activity and innovative medical radioisotopes. However, the lack of experimental data on reaction cross sections for photonuclear reactions of medical radioisotopes of interest has severely limited the development and production of photonuclear transmutation medical radioisotopes. In this study, the entire process of the generation, decay, and measurement of medical radioisotopes was simulated using online gamma activation and offline gamma measurements combined with a shielding gammaray spectrometer. Based on a quasi-monochromatic gamma beam from the Shanghai Laser Electron Gamma Source (SLEGS), the feasibility of the measurement of production cross section for surveyed medical isotopes was simulated, and specific solutions for measuring medical radioisotopes with low production cross sections were provided. The feasibility of this method for high precision measurements of the reaction cross section of medical radioisotopes was demonstrated.

  • Bunch-length measurement at a bunch-by-bunch rate based on time–frequency-domain joint analysis techniques and its application

    分类: 核科学技术 >> 核科学与技术 提交时间: 2024-03-12

    摘要: This paper presents a new technique for measuring the bunch length of a high-energy electron beam at a bunch-by-bunch rate in storage rings. This technique uses the time–frequency-domain joint analysis of the bunch signal to obtain bunch-by-bunch and turn-by-turn longitudinal parameters, such as bunch length and synchronous phase. The bunch signal is obtained using a button electrode with a bandwidth of several gigahertz. The data acquisition device was a high-speed digital oscilloscope with a sampling rate of more than 10 GS/s, and the single-shot sampling data buffer covered thousands of turns. The bunch length and synchronous phase information were extracted via offline calculations using Python scripts. The calibration coefficient of the system was determined using a commercial streak camera. Moreover, this technique was tested on two different storage rings and successfully captured various longitudinal transient processes during the harmonic cavity debugging process at the Shanghai Synchrotron Radiation Facility (SSRF), and longitudinal instabilities were observed during the single bunch accumulation process at Hefei Light Source (HLS). For Gaussian-distribution bunches, the uncertainty of the bunch phase obtained using this technique was better than 0.2 ps, and the bunch length uncertainty was better than 1 ps. The dynamic range exceeded 10 ms. This technology is a powerful and versatile beam diagnostic tool that can be conveniently deployed in high-energy electron storage rings.

  • Feasibility of medical radioisotope production based on the proton beams at China Spallation Neutron Source

    分类: 物理学 >> 核物理学 提交时间: 2024-03-10

    摘要: Theutilization of a proton beam fromthe China Spallation Neutron Source (CSNS) for producingmedical radioisotopes is appealingowing toits high current intensity and high energy. The medical isotope production based on the proton beam at the CSNS is significantfor the development of futureradiopharmaceuticals, particularly for the α-emitting radiopharmaceuticals.The production yield and activity of typical medical isotopes wereestimated using theFLUKA simulation. The results indicate that the 300-MeV proton beam with a power of 100 kW at CSNS-II ishighly suitable for proof-of-principle studies of most medical radioisotopes. In particular, this proton beam offers tremendous advantages for the large-scale production of alpha radioisotopes, such as 225Ac, whose theoretical production yield can reach approximately57 Ci/week. Based on theseresults, we provideperspectives on the use ofCSNS proton beams to produce radioisotopes for medical applications.

  • Opportunities for production and property research of neutron-rich nuclei around N=126 at HIAF

    分类: 物理学 >> 核物理学 提交时间: 2024-03-09

    摘要: The study of nuclide production and its properties in the N=126 neutron-rich region is the frontier and hot topic in nuclear physics and astrophysics research. The upcoming High energy FRagment Separator (HFRS) at the High Intensity heavy-ion Accelerator Facility (HIAF), an in-flight separator at relativistic energies, is characterized by high beam intensity, large ion-optical acceptance, high magnetic rigidity, and high momentum resolution power. It provides an opportunity for the study of the production and properties of neutron-rich nuclei around N=126. In this paper, an experimental scheme is proposed to produce the neutron-rich nuclei around N=126 and simultaneously measure their mass and lifetime based on the HFRS separator, and the feasibility of this scheme is evaluated by the simulations. The results show that under the high resolution optical mode many new neutron-rich nuclei approaching the r-process abundance peak around A=195 can be produced for the first time, and many nuclei with unknown mass and lifetime can be produced with high statistics. Using the time-of-flight corrected by the measured dispersive position and the energy loss information, the cocktails produced from the 208Pb fragmentation can be unambiguously identified. Moreover, the masses of some neutron-rich nuclei in the vicinity of N=126 can be measured with high precision using the time-of-flight magnetic rigidity technique. This indicates that the HIAF-HFRS facility has potential for the production and property research of neutron-rich nuclei around N=126, which is of great significance for expanding chart of nuclides, developing nuclear theories, and understanding the origin of heavy elements in the universe.

  • Molecular basis of ligand recognition and activation of succinate receptor

    分类: 药物科学 >> 结构生物学 提交时间: 2024-02-29

    摘要: Succinic acid, a tricarboxylic acid (TCA) cycle intermediate, significantly influences mitochondrial reactive oxygen species homeostasis through the G protein-coupled succinate receptor (SUCR1, also called GPR91), linking it to various physiological and pathological processes. Despite SUCR1’s pivotal role in mediating effects leading to liver fibrosis, hypertension, angiogenesis, inflammation, and offering a therapeutic target for multiple diseases, its activation mechanism by diverse ligands and interaction with downwards G protein remains poorly understood. This study presents the cryo-electron microscopy (cryo-EM) structures of SUCR1 in complex with inhibitory G protein (Gi) bound to succinic acid, maleic acid, and compound 31, a high-affinity agonist. These structures elucidate the distinct ligand binding modes, uncover the activation signal cascade, and detail the G protein coupling mechanism of SUCR1. Our findings provide a comprehensive structural basis for SUCR1 activation, paving the way for structure-based drug design aimed at SUCR1-related pathologies.

  • Reevaluating GPR30: A Paradigm Shift from Estrogen Receptor to Unique Hydrophilic Ligand Activation

    分类: 药物科学 >> 结构生物学 提交时间: 2024-02-24

    摘要: The orphan receptor GPR30, previously classified as a G protein-coupled estrogen receptor (GPER), has been a subject of debate regarding its ligand specificity. Through an integrative approach combining structure elucidation, biochemical binding, and cell signaling assays, we demonstrate that estrogen does not directly bind to or activate GPR30. Cryo-EM structures of GPR30 reveal an unexpected hydrophilic ligand-binding pocket, with striking differences from classical hydrophobic steroid-binding sites, inconsistent with estrogen binding. We further confirmed hydrophilic agonists like Lys05 as true activators of GPR30, providing structural insights into their binding mechanism and receptor activation. Our findings necessitate a paradigm shift in defining GPR30’s role in estrogen signaling, indicating that its activation occurs through mechanisms independent of estrogen binding. This study opens new avenues for developing targeted GPR30 ligands and reinterpreting its role in estrogen-mediated processes.