A5069646016- ATP Synthase and ATPases Research
- Mitochondrial Function and Pathology
- Ion channel regulation and function
- Drug Transport and Resistance Mechanisms
- DNA and Nucleic Acid Chemistry
- Amino Acid Enzymes and Metabolism
- RNA and protein synthesis mechanisms
- Antibiotic Resistance in Bacteria
- Calcium signaling and nucleotide metabolism
- Lipid Membrane Structure and Behavior
- Cancer, Stress, Anesthesia, and Immune Response
- Anesthesia and Neurotoxicity Research
- Fuel Cells and Related Materials
- Pain Mechanisms and Treatments
- Photosynthetic Processes and Mechanisms
- Cancer therapeutics and mechanisms
- Bacterial Genetics and Biotechnology
- Enzyme Structure and Function
- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- Force Microscopy Techniques and Applications
- Immune Cell Function and Interaction
- Genetics, Bioinformatics, and Biomedical Research
- Protein Structure and Dynamics
- Autophagy in Disease and Therapy
National Institutes of Health
2014-2024
National Heart Lung and Blood Institute
2014-2024
Roivant Sciences (United States)
2021-2022
Fudan University
2020-2021
Sun Yat-sen University
2020-2021
Zhongshan Hospital
2020-2021
The First Affiliated Hospital, Sun Yat-sen University
2020-2021
Shanghai Medical College of Fudan University
2020
Fudan University Shanghai Cancer Center
2020
Huazhong University of Science and Technology
2017-2020
Mitochondrial adenosine triphosphate (ATP) synthase comprises a membrane embedded Fo motor that rotates to drive ATP synthesis in the F1 subunit. We used single-particle cryo-electron microscopy (cryo-EM) obtain structures of full complex lipid bilayer absence or presence inhibitor oligomycin at 3.6- and 3.8-angstrom resolution, respectively. To limit conformational heterogeneity, we locked rotor single conformation by fusing F6 subunit stator with δ rotor. Assembly enzyme F6-δ fusion caused...
Autophagy is a catabolic process involving capture of cytoplasmic materials into double-membraned autophagosomes that subsequently fuse with lysosomes for degradation the by lysosomal hydrolases. One least understood components autophagy machinery transmembrane protein ATG9. Here, we report cryoelectron microscopy structure human ATG9A isoform at 2.9-Å resolution. The reveals fold homotrimeric domain-swapped architecture, multiple membrane spans, and network branched cavities, consistent...
Membrane transporters of the RND superfamily confer multidrug resistance to pathogenic bacteria, and are essential for cholesterol metabolism embryonic development in humans. We use high-resolution X-ray crystallography computational methods delineate mechanism homotrimeric RND-type proton/drug antiporter AcrB, active component major efflux system AcrAB-TolC Escherichia coli, one most complex intriguing membrane known date. Analysis wildtype AcrB four functionally-inactive variants reveals...
Bruton tyrosine kinase (BTK) is present in a wide variety of cells and may thus have important non-B cell functions. Here, we explored the function this macrophages with studies its regulation NLR family, pyrin domain-containing 3 (NLRP3) inflammasome. We found that bone marrow-derived (BMDMs) from BTK-deficient mice or monocytes patients X-linked agammaglobulinemia (XLA) exhibited increased NLRP3 inflammasome activity; was also case for BMDMs exposed to low doses BTK inhibitors such as...
Targeted protein degradation (TPD) is a promising approach in drug discovery for degrading proteins implicated diseases. A key step this process the formation of ternary complex where heterobifunctional molecule induces proximity an E3 ligase to interest (POI), thus facilitating ubiquitin transfer POI. In work, we characterize 3 steps TPD process. (1) We simulate SMARCA2 bromodomain and VHL by combining hydrogen-deuterium exchange mass spectrometry with weighted ensemble molecular dynamics...
Pathological metabolic conditions such as ischemia induce the rupture of mitochondrial envelope and release pro-apoptotic proteins, leading to cell death. At onset this process, inner membrane becomes depolarized permeable osmolytes, proposedly due opening a non-selective protein channel unknown molecular identity. A recent study purports that channel, referred Mitochondrial Permeability Transition Pore (MPTP), is formed within c-subunit ring ATP synthase, upon its dissociation from...
Abstract Cognitive impairment is one of the most common complications associated with chronic pain. Almost 20% pain patients suffer from cognitive impairment, which may substantially influence their quality life. Levels major excitatory neurotransmitters in central nervous system and alterations glutamatergic function sensory pathway. In this study, we adopted spared nerve injury model to establish progress investigated mechanism underlying aspect related it. At behavioral level, using...
That channels and transporters can influence the membrane morphology is increasingly recognized. Less appreciated that extent free-energy cost of these deformations likely varies among different functional states a protein, thus, they might contribute significantly to defining its mechanism. We consider trimeric Na+-aspartate symporter GltPh, homolog an important class neurotransmitter transporters, whose mechanism entails one most drastic structural changes known. Molecular simulations...
Significance The TRPV1 channel integrates noxious stimuli from multiple sources to evoke an appropriate pain response. However, while different distinct activation, the underlying molecular mechanisms remain unclear. Here, we aim at elucidating structural determinants that regulate responses two toxins: capsaicin and double-knot toxin (DkTx). We found pore turret domain imposes opposite effects on these toxins. While it restricts ion conductance of DkTx-evoked current, stabilizes open state...
Abstract Bedaquiline (BDQ, Sirturo) has been approved to treat multidrug resistant forms of Mycobacterium tuberculosis . Prior studies suggested that BDQ was a selective inhibitor the ATP synthase from M. However, Sirturo treatment leads an increased risk cardiac arrhythmias and death, raising concern this adverse effect results inhibition at secondary site. Here we show is potent yeast human mitochondrial synthases. Single-particle cryo-EM reveals site partially overlaps with oligomycin....
Summary Aim Multifactors contribute to the development of postoperative cognitive dysfunction ( POCD ), which most important mechanism is neuroinflammation. Prostaglandin E2 PGE 2) a key neuroinflammatory molecule and could modulate hippocampal synaptic transmission plasticity. This study was designed investigate whether 2 its receptors signaling pathway were involved in pathophysiology . Methods Sixteen‐month old male C57 BL /6J mice exposed laparotomy. Cognitive function evaluated by fear...
Diabetic nephropathy (DN) has become the common and principal microvascular complication of diabetes that could lead to end-stage renal disease. It was reported endothelial-to-mesenchymal transition (EndMT) in glomeruli plays an important role DN. Enolase1 (ENO1) Lysine Methyltransferase 5A (KMT5A) were found modulate epithelial-to-mesenchymal some situations. In present study, we speculated KMT5A regulates ENO1 transcript, thus participating hyperglycemia-induced EndMT Our study represented...
Structures of the human lysosomal K + channel transmembrane protein 175 (TMEM175) in open and closed states revealed a novel architecture lacking canonical selectivity filter motif present previously known structures. A hydrophobic constriction composed four isoleucine residues was resolved pore proposed to serve as gate state, confer ion state. Here, we achieve higher-resolution structures employ molecular dynamics simulations analyze conducting properties putative demonstrating that it is...
Abstract Aims Perioperative neurocognitive disorders (PND) are associated with cognitive impairment in the preoperative or postoperative period, and neuroinflammation is thought to be most important mechanisms especially during period. The GABAergic system easily disrupted by neuroinflammation. This study investigated impact of on PND after anesthesia surgery. Methods An animal model laparotomy inhalation 16‐month‐old mice was addressed. Effects were assessed using biochemical analysis....
Significance MATE transporters deplete the bacterial cytosol of natural and human-made antibiotics contribute to confer multidrug resistance a wide range human pathogens. Despite being compelling pharmacological target, little is known about their molecular mechanism. Based upon crystallographic computational data, we gain insights into mechanism by which drug efflux energized transmembrane electrochemical gradients ions identifying Na + -binding site in N-terminal domain transporter. This...
Transmembrane protein 175 (TMEM175) is an evolutionarily distinct lysosomal cation channel whose mutation associated with the development of Parkinson’s disease. Here, we present a cryoelectron microscopy structure and molecular simulations TMEM175 bound to 4-aminopyridine (4-AP), only known small-molecule inhibitor broad K + inhibitor, as well drug approved by Food Drug Administration against multiple sclerosis. The shows that 4-AP, mode action had not been previously visualized, binds near...
Tobacco mosaic virus (TMV) causes significant losses in many economically important crops. Contaminated soils may play roles as reservoirs and sources of transmission for TMV. In this study we report the development an immunocapture real-time RT-PCR (IC-real-time RT-PCR) assay direct detection TMV without RNA isolation. A series infected leaf sap dilutions 1:101, 1:102, 1:103, 1:104, 1:105 1:106 (w/v, g/mL) were added to one gram soil. The reactivity DAS-ELISA conventional was range 1:102...
Human genetic studies recently identified an association of SNPs in the 17-β hydroxysteroid dehydrogenase 13 (HSD17B13) gene with alcoholic and nonalcoholic fatty liver disease development. Mutant HSD17B13 variants devoid enzymatic function have been demonstrated to be protective from cirrhosis cancer, supporting development as a promising therapeutic target. Previous that is lipid droplet (LD)-associated protein. However, critical domains drive LD targeting or determine activity yet...
Purpose: To explore whether alkali burn causes corneal neuropathic pain and activates the matrix in central nervous system mice. Methods: A mouse model (grade II) was used. The mechanical threshold cauterized area tested using Von Frey hairs. Spontaneous behavior investigated with conditioned place preference. Phosphor extracellular signal–regulated kinase (ERK), which is a marker for neuronal activation chronic processing, several representative areas of matrix: 2 regions spinal trigeminal...