A5031502585- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Pancreatic function and diabetes
- HIV Research and Treatment
- Hepatitis B Virus Studies
- Hepatitis C virus research
- Immune Cell Function and Interaction
- PI3K/AKT/mTOR signaling in cancer
- Monoclonal and Polyclonal Antibodies Research
- Metabolism, Diabetes, and Cancer
- Soybean genetics and cultivation
- Protein Kinase Regulation and GTPase Signaling
- T-cell and B-cell Immunology
- HIV/AIDS drug development and treatment
- Legume Nitrogen Fixing Symbiosis
- Tryptophan and brain disorders
- DNA Repair Mechanisms
- Advanced Proteomics Techniques and Applications
- RNA Interference and Gene Delivery
- Cellular transport and secretion
- Ion channel regulation and function
- Calcium signaling and nucleotide metabolism
- Agronomic Practices and Intercropping Systems
- Virus-based gene therapy research
- RNA Research and Splicing
Chongqing University of Science and Technology
2024
Huashan Hospital
2024
Fudan University
2024
State Key Laboratory of Genetic Engineering
2024
Traditional Chinese Medicine Hospital of Kunshan
2023-2024
Nanjing University of Chinese Medicine
2024
Shanghai University of Traditional Chinese Medicine
2023-2024
Shenzhen Institutes of Advanced Technology
2024
Nanjing Normal University
2018-2024
Northwest A&F University
2018-2024
A major challenge of the post-genomics era is to define connectivity protein phosphorylation networks. Here, we quantitatively delineate insulin signaling network in adipocytes by high-resolution mass spectrometry-based proteomics. These data reveal complexity intracellular phosphorylation. We identified 37,248 sites on 5,705 proteins this single-cell type, with approximately 15% responding insulin. integrated these large-scale phosphoproteomics using a machine learning approach predict...
The mechanistic target of rapamycin complex 2 (mTORC2) regulates cell survival and cytoskeletal organization by phosphorylating its AGC kinase substrates; however, little is known about the regulation mTORC2 itself. It was previously reported that Akt phosphorylates subunit SIN1 at T86, activating through a positive feedback loop, though another study S6K same site, inhibiting activity. We performed extensive analysis phosphorylation upon inhibition Akt, S6K, mTOR under diverse cellular...
Smac mimetic compounds targeting the inhibitor of apoptosis proteins (IAP) baculoviral IAP repeat-3 domain are presumed to reduce threshold for apoptotic cell death by alleviating caspase-9 repression. We explored this tenet in an unbiased manner searching small interfering RNAs that able confer resistance compound LBW242. Among screening hits were multiple components tumor necrosis factor alpha (TNFalpha) signaling pathway as well X-linked (XIAP) itself. Here, we show a subset highly...
Many human monoclonal antibodies that neutralize multiple clades of HIV-1 are polyreactive and bind avidly to mammalian autoantigens. Indeed, the generation neutralizing 2F5 4E10 epitopes gp41 in man may be proscribed by immune tolerance because mice expressing VH VL regions have a block B cell development is characteristic central tolerance. This developmental blockade implies presence tolerizing autoantigens mimicked membrane-proximal external region gp41. We identify kynureninase (KYNU)...
It is generally acknowledged that human broadly neutralizing antibodies (bNAbs) capable of multiple HIV-1 clades are often polyreactive or autoreactive. Whereas polyreactivity autoreactivity has been proposed to be crucial for neutralization breadth, no systematic, quantitative study self-reactivity among nonneutralizing Abs (nNAbs) performed determine whether poly- in bNAbs a consequence chronic antigen (Ag) exposure and/or inflammation fundamental property neutralization. Here, we use...
Induction of broadly neutralizing antibodies (bnAbs) is a goal HIV-1 vaccine development. Antibody 10E8, reactive with the distal portion membrane-proximal external region (MPER) gp41, neutralizing. However, ontogeny MPER and relationship memory B cell to plasma bnAbs are poorly understood. HIV-1-specific flow sorting proteomic identification anti-MPER from an HIV-1-infected individual were used isolate same clonal lineage. Structural analysis demonstrated that cells recognized envelope gp41...
Abstract Heteroaryldihydropyrimidine (HAP) and sulfamoylbenzamide (SBA) are promising non-nucleos(t)ide HBV replication inhibitors. HAPs known to promote core protein mis-assembly, but the molecular mechanism of abnormal assembly is still elusive. Likewise, status induced by SBA remains unknown. Here we show that SBA, unlike HAP, does not mis-assembly. Interestingly, two reference compounds HAP_R01 SBA_R01 bind same pocket at dimer-dimer interface in crystal structures Y132A hexamer. The...
Abstract Protein oxidation sits at the intersection of multiple signalling pathways, yet magnitude and extent crosstalk between other post-translational modifications remains unclear. Here, we delineate global changes in adipocyte networks following acute oxidative stress reveal considerable cysteine phosphorylation-based signalling. Oxidation key regulatory kinases, including Akt, mTOR AMPK influences fidelity rather than their absolute activation state, highlighting an unappreciated...
DNA double-strand breaks (DSBs) are fatal lesions and activate a rapid damage response. However, the earliest stage of DSB sensing remains elusive. Here, we report that PARP1 Ku70/80 complex localize to considerably earlier than other sensors. Using super-resolved fluorescent particle tracking, further examine relocation kinetics single DSB, find recruited almost at same time. Notably, only occupies exclusively in G1 phase; whereas competes with S/G2 phase. Moreover, phase, removes through...
Broadly HIV-1-neutralizing antibodies (BnAbs) display one or more unusual traits, including a long heavy chain complementarity-determining region 3 (HCDR3), polyreactivity, and high levels of somatic mutations. These shared characteristics suggest that BnAb development might be limited by immune tolerance controls. It has been postulated HIV-1-infected individuals with autoimmune disease defective mechanisms may produce BnAbs readily than those without diseases. In this study, we identified...
The effect of acute inhibition both mTORC1 and mTORC2 on metabolism is unknown. A single injection the mTOR kinase inhibitor, AZD8055, induced a transient, yet marked increase in fat oxidation insulin resistance mice, whereas inhibitor rapamycin had no effect. but not reduced insulin-stimulated glucose uptake into incubated muscles, despite normal GLUT4 translocation muscle cells. AZD8055 inhibited glycolysis MEF Abrogation activity by SIN1 deletion impaired KO MEFs. Re-expression wildtype...
Targeting the capsid protein of hepatitis B virus (HBV) and thus interrupting normal formation have been an attractive approach to block replication HBV viruses. We carried out multidimensional structural optimizations based on heteroaryldihydropyrimidine (HAP) analogue Bay41-4109 (1) identified a novel series inhibitors that demonstrated promising cellular selectivity indexes, metabolic stabilities, in vitro safety profiles. Herein we disclose design, synthesis, structure-activity...
A mass spectrometry method may enable the simultaneous and rapid quantification of multiple phosphorylation events in samples.
Abstract Calcium/calmodulin-dependent protein serine kinase (CASK) is a key player in vesicle transport and release neurons. However, its precise role, particularly nonneuronal systems, incompletely understood. We report that CASK functions as an important regulator of insulin secretion. depletion mouse islets/β cells substantially reduces secretion docking/fusion. forms ternary complex with Mint1 Munc18-1, this event regulated by glucose stimulation β cells. The crystal structure the...
The phosphoinositide 3-kinase (PI3K)-Akt network is tightly controlled by feedback mechanisms that regulate signal flow and ensure fidelity. A rapid overshoot in insulin-stimulated recruitment of Akt to the plasma membrane has previously been reported, which indicative negative operating on acute timescales. Here, we show itself engages this phosphorylating insulin receptor substrate (IRS) 1 2 a number residues. Phosphorylation results depletion membrane-localised IRS1/2, reducing pool...
Soybean (Glycine max) is highly sensitive to photoperiod, which affects flowering time and plant architecture thus limits the distribution range of elite soybean cultivars. The major maturity gene E1 confers most prominent effect on photoperiod sensitivity, but its downstream signaling pathway remains largely unknown. Here, we confirm that encoded protein a transcriptional repressor. expression seven GmMDE genes max MADS-box downregulated by E1) was suppressed when overexpressed promoted...
Described herein is the first-time disclosure of Linvencorvir (RG7907), a clinical compound and hepatitis B virus (HBV) core protein allosteric modulator, for treatment chronic HBV infection. Built upon structure hetero aryl dihydropyrimidine, RG7907 was rationally designed by combining all drug-like features low CYP3A4 induction, potent anti-HBV activity, high metabolic stability, hERG liability, favorable animal pharmacokinetic (PK) profiles. In particular, chemistry strategy to mitigate...
Transthyretin (TTR) is a transport protein for thyroxine and, in association with retinol-binding protein, retinol, mainly existing as tetramer vivo . We now demonstrate that TTR has positive role pancreatic β-cell stimulus-secretion coupling. promoted glucose-induced increases cytoplasmic free Ca 2+ concentration ([Ca ] i ) and insulin release. This resulted from direct effect on electrical activity voltage-gated channels. also protected against apoptosis. The of was decreased, whereas...
Interferon-α (IFN-α) is used to treat chronic hepatitis B virus (HBV) infection, but only 20%-40% of patients respond well. Clinical observations have suggested that HBV genotype associated with the response IFN therapy; however, its role in viral responsiveness HBV-infected hepatocytes remains unclear. Here, we produced infectious virions genotypes A D infect three well-recognized cell-culture-based infection systems, including primary human (PHH), differentiated HepaRG (dHepaRG), and...
Described herein are the discovery and structure–activity relationship (SAR) studies of third-generation 4-H heteroaryldihydropyrimidines (4-H HAPs) featuring introduction a C6 carboxyl group as novel HBV capsid inhibitors. This new series HAPs showed improved anti-HBV activity better drug-like properties compared to first- second-generation HAPs. X-ray crystallographic study analogue 12 (HAP_R01) with Cp149 Y132A mutant hexamer clearly elucidated role played for increased binding affinity,...
Mutations of the cyclin-dependent kinase-like 5 (CDKL5) gene cause severe neurodevelopmental disorders characterized by intractable epilepsy, intellectual disability, and autism. Multiple mouse models generated for mechanistic studies have exhibited phenotypes similar to some human pathological features, but none has developed one major symptoms affecting CDKL5 deficiency disorder (CDD) patients: recurrent seizures. As disrupted neuronal excitation/inhibition balance is closely associated...