A5101753415- Drug Transport and Resistance Mechanisms
- Pharmacogenetics and Drug Metabolism
- Computational Drug Discovery Methods
- Lipid Membrane Structure and Behavior
- Alzheimer's disease research and treatments
- RNA and protein synthesis mechanisms
- Chemical Synthesis and Analysis
- HIV/AIDS drug development and treatment
- Analytical Chemistry and Chromatography
- Rabbits: Nutrition, Reproduction, Health
- Protein Structure and Dynamics
- DNA and Nucleic Acid Chemistry
- Trace Elements in Health
- Parkinson's Disease Mechanisms and Treatments
- Receptor Mechanisms and Signaling
- Supramolecular Self-Assembly in Materials
- Adipose Tissue and Metabolism
- Cancer therapeutics and mechanisms
- Crystallization and Solubility Studies
- ATP Synthase and ATPases Research
- Mechanical Circulatory Support Devices
- Peptidase Inhibition and Analysis
- Biochemical and Molecular Research
- X-ray Diffraction in Crystallography
- Metal complexes synthesis and properties
Weifang People's Hospital
2019-2025
Scripps Research Institute
2015-2024
Suihua University
2024
Guiyang Medical University
2016-2023
Hunan Normal University
2022
Hunan Provincial People's Hospital
2022
The Fourth People's Hospital of Zibo City
2020
Doshisha Women's College of Liberal Arts
2020
Albany College of Pharmacy and Health Sciences
2020
Second Xiangya Hospital of Central South University
2017-2019
P-glycoprotein (P-gp) detoxifies cells by exporting hundreds of chemically unrelated toxins but has been implicated in multidrug resistance (MDR) the treatment cancers. Substrate promiscuity is a hallmark P-gp activity, thus structural description poly-specific drug-binding important for rational design anticancer drugs and MDR inhibitors. The x-ray structure apo at 3.8 angstroms reveals an internal cavity approximately 6000 cubed with 30 angstrom separation two nucleotide-binding domains....
Anfinsen showed that a protein's fold is specified by its sequence. Although it clear why mutant proteins form amyloid, harder to rationalize wild-type protein adopts native conformation in most individuals, but misfolds minority of others, what should be common extracellular environment. This discrepancy suggests another event likely triggers misfolding sporadic amyloid disease. One possibility an abnormal metabolite, generated only some covalently modifies the or peptide and causes...
P-glycoprotein (P-gp) is a transporter of great clinical and pharmacological significance. Several structural studies P-gp its homologs have provided insights into transport cycle, but questions remain regarding how recognizes diverse substrates substrate binding coupled to ATP hydrolysis. Here, four new co-crystal structures with series rationally designed ligands are presented. It observed that the certain ligands, including an ATP-hydrolysis stimulator, produces large conformational...
Abstract Gap junction channels mediate intercellular signalling that is crucial in tissue development, homeostasis and pathologic states such as cardiac arrhythmias, cancer trauma. To explore the mechanism by which Ca 2+ blocks communication during injury, we determined X-ray crystal structures of human Cx26 gap channel with without bound . The two were nearly identical, ruling out both a large-scale structural change local steric constriction pore. coordination sites reside at interfaces...
Significance Membrane proteins (MPs) perform a variety of essential cellular functions, account for about one-third encoded in genomes, and comprise more than one-half human drug targets. High-resolution structures are to understand the underlying molecular mechanisms MPs facilitate structure-based design efforts. Detergents indispensible solubilization MPs, but they tend destabilize often impede growth well-ordered protein crystals. We describe class structurally unique detergents,...
P450 2D6 contributes significantly to the metabolism of >15% 200 most marketed drugs. Open and closed crystal structures thioridazine complexes were obtained using different crystallization conditions. The protonated piperidine moiety forms a charge-stabilized hydrogen bond with Asp-301 in active sites both complexes. more open conformation exhibits second molecule bound an expanded substrate access channel antechamber its forming Glu-222. Incubation crystalline complex alternative ligands,...
Abstract BACKGROUND Changes in antioxidant activity of fruit during fermentation are related to changes the composition phenolic acids and flavonoids. In this study, we investigated effects Lactobacillus plantarum on profile, activities, metabolites kiwifruit pulp. RESULTS increased scavenging 1‐diphenyl‐2‐picrylhydrazyl (DPPH) 2,20‐azinobis (3‐ethylbenzothiazoline‐6‐sulphonic acid) diammonium salt (ABTS) radicals. The content phenolics flavonoids was after fermentation. Correlation analysis...
The process of amyloid formation by the β peptide (Aβ), i.e., misassembly Aβ peptides into soluble quaternary structures and, ultimately, fibrils, appears to be at center Alzheimer's disease (AD) pathology. We have shown that abnormal oxidative metabolites, including cholesterol-derived aldehydes, modify and accelerate early stages amyloidogenesis (the spherical aggregates). This process, which we termed metabolite-initiated protein misfolding, could explain why hypercholesterolemia...
An added dimension: Amphiphiles with two-dimensional hydrophobic and hydrophilic faces represent a departure from traditional one-dimensional polar-head/nonpolar-tail molecules for the stabilization of integral membrane proteins. A prototypical example this design has been synthesized cholic acid (see picture), was successfully used in two proteins (represented by blue/green cylinder).
The structure of the K262R genetic variant human cytochrome P450 2B6 in complex with inhibitor 4-(4-chlorophenyl)imidazole (4-CPI) has been determined using X-ray crystallography to 2.0-A resolution. Production diffraction quality crystals was enabled through a combination protein engineering, chaperone coexpression, modifications purification protocol, and use unique facial amphiphiles during crystallization. 2B6-4-CPI is virtually identical rabbit 2B4 bound same respect arrangement...
P-glycoprotein (Pgp) is a prototypical ATP-binding cassette (ABC) transporter of great biological and clinical significance.Pgp confers cancer multidrug resistance mediates the bioavailability pharmacokinetics many drugs (Juliano Ling, 1976; Ueda et al., 1986; Sharom, 2011). Decades structural biochemical studies have provided insights into how Pgp binds diverse compounds (Loo Clarke, 2000; Loo 2009; Aller Alam 2019; Nosol 2020; Chufan 2015), but they are translocated through membrane has...
Structures of human cytochrome P450 2B6 and rabbit 2B4 in complex with two molecules the calcium channel blocker amlodipine have been determined by X-ray crystallography. The presence drug suggests clear substrate access channels each P450. According to a previously established nomenclature, were trapped pathway 2f 2a or 2B4. These pathways overlap for part length then diverge as they extend toward protein surface. A described solvent was also found enzyme. results indicate that key residues...
Human P-glycoprotein (P-gp) controls drugs bioavailability by pumping structurally unrelated out of cells. The X-ray structure the mouse P-gp ortholog has been solved, with two SSS enantiomers or one RRR enantiomer selenohexapeptide inhibitor QZ59, found within putative drug-binding pocket (Aller SG, Yu J, Ward A, Weng Y, Chittaboina S, Zhuo R, Harrell PM, Trinh YT, Zhang Q, Urbatsch IL et al. (2009). Science 323, 1718-1722). This offered first opportunity to localize well-known H and R...
Numerous cytochrome P450 (CYP) 2B6 substrates including drugs and environmental chemicals are halogenated. To assess the role of halogen−π bonds in substrate selectivity orientation active site, structures four CYP2B6 monoterpenoid complexes were solved by X-ray crystallography. Bornyl bromide exhibited dual orientations site with predominant revealing a bromine−π bond Phe108 side chain. Bornane demonstrated two equal occupancy; both, C2 atom that bears bromine bornyl was displaced more than...
Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), can reduce cardiovascular events and mortality in patients with heart failure. A number mechanisms have been proposed to explain the beneficial effects SGLT2 inhibitors. The purpose this study was determine whether dapagliflozin improve pulmonary vascular remodelling efficacy as an add-on therapy sildenafil rats arterial hypertension (PAH).A monocrotaline (MCT)-induced PAH rat model used our study. MCT-injected...
Conservative mutation of transthyretin's surface residues can predispose an individual to familial amyloidosis by dramatically changing the energetics misfolding. Senile systemic (SSA), however, cannot be explained in this fashion because wild-type (WT) transthyretin (TTR) misfolds and misassembles into amyloid. Since various modifications SH functionality Cys10 have been reported humans, we sought understand extent which these alter stability WT TTR as a possible explanation for SSA....