A5062493231- Cholinesterase and Neurodegenerative Diseases
- Computational Drug Discovery Methods
- Protein Structure and Dynamics
- Chemical Synthesis and Analysis
- Neuroscience and Neuropharmacology Research
- Neuropeptides and Animal Physiology
- Chemical synthesis and alkaloids
- Enzyme Structure and Function
- Alzheimer's disease research and treatments
- Nicotinic Acetylcholine Receptors Study
- Pesticide Exposure and Toxicity
- Receptor Mechanisms and Signaling
- RNA and protein synthesis mechanisms
- Peptidase Inhibition and Analysis
- Crystallography and molecular interactions
- Insect and Pesticide Research
- Biochemical and Structural Characterization
- Enzyme function and inhibition
- Botulinum Toxin and Related Neurological Disorders
- Mitochondrial Function and Pathology
- Cancer therapeutics and mechanisms
- Chemical Reaction Mechanisms
- Insect Pest Control Strategies
- Neuroinflammation and Neurodegeneration Mechanisms
- Insect Resistance and Genetics
Klinik und Poliklinik für Kinder- und Jugendmedizin
2025
Hubei University of Technology
2025
Guangxi Normal University
2025
Mayo Clinic
2014-2024
WinnMed
2004-2024
Ningbo Institute of Industrial Technology
2024
Chinese Academy of Sciences
2024
Nanjing University of Chinese Medicine
2024
Changzhou University
2024
Mayo Clinic in Arizona
2004-2023
We report highly potent, selective, and low cost bifunctional acetylcholinesterase (AChE) inhibitors developed by our two-step prototype optimization strategy utilizing computer modeling of ligand docking with target proteins: 1) identify affinity sites normally missed x-ray crystallography; 2) design analogs capable simultaneous binding at the computer-determined site x-ray-identified high site. Applying this to 9-amino-1,2,3,4-tetrahydroacridine (THA), a drug for Alzheimer's disease, we...
The X-ray crystal structures were solved for complexes with Torpedo californica acetylcholinesterase of two bivalent tacrine derivative compounds in which the rings separated by 5- and 7-carbon spacers. spacer spans length active-site gorge, making sandwich interactions aromatic residues both catalytic anionic site (Trp84 Phe330) at bottom gorge peripheral near its mouth (Tyr70 Trp279). 5-carbon interacts a similar manner but shorter tether precludes interaction site. Although upper group...
The mechanism by which the proapoptotic Bcl-2 family members Bax and Bak release cytochrome c from mitochondria is incompletely understood. In this paper, we show that activator BH3-only proteins bind tightly but transiently to hydrophobic BH3-binding groove induce oligomerization, liposome permeabilization, mitochondrial release, cell death. Analysis surface plasmon resonance indicated initial binding of occurred with similar kinetics or without detergent lipids, these reagents increase...
We compared biological functions of two acetylcholinesterase genes (TcAce1 and TcAce2) in Tribolium castaneum, a globally distributed major pest stored grain products an emerging model organism, by using RNA interference. Although both expressed at all developmental stages mainly the brain, transcript level TcAce1 was 1.2- to 8.7-fold higher than that TcAce2, depending on stages. Silencing 20-day larvae led 100% mortality within weeks after eclosion increased larval susceptibilities...
Development of therapeutic strategies to prevent Alzheimer's Disease (AD) is great importance. We show that mild inhibition mitochondrial complex I with small molecule CP2 reduces levels amyloid beta and phospho-Tau averts cognitive decline in three animal models familial AD. Low-mass molecular dynamics simulations biochemical studies confirmed competes flavin mononucleotide for binding the redox center leading elevated AMP/ATP ratio activation AMP-activated protein kinase neurons mouse...
Significance Butyrylcholinesterase (BChE), a common plasma enzyme, has been known for decades but its real physiological roles are just beginning to emerge. Although BChE eliminates the neurotransmitter acetylcholine, it is not vital locomotion, cognition, or other cholinergic functions. Nevertheless, we now find that circulating large impact on aggressive behavior in mice attributable ability inactivate ghrelin, peptide hormone involved hunger, feeding, and stress. A key observation was...
ABSTRACT Understanding how some HIV-infected cells resist the cytotoxicity of HIV replication is crucial to enabling cure efforts. killing CD4 T that replicate can involve protease-mediated cleavage procaspase 8 generate a fragment (Casp8p41) directly binds and activates mitochondrial proapoptotic protein BAK. Here, we demonstrate Casp8p41 also with nanomolar affinity antiapoptotic Bcl-2, which sequesters prevents apoptosis. Further, show central memory (T CM ) from individuals have...
Rationale: Bronchiectasis is a pathological dilatation of the bronchi in respiratory airways associated with environmental or genetic causes (e.g., cystic fibrosis, primary ciliary dyskinesia and immunodeficiency disorders), but most cases remain idiopathic. Objectives: To identify novel defects unsolved bronchiectasis presenting severe rhinosinusitis, nasal polyposis, pulmonary Pseudomonas aeruginosa infection. Methods: DNA was analyzed by next-generation targeted Sanger sequencing. RNA...
Abstract I report herein two 2.0 ns (1.0 fs time step) MD simulations of zinc complexes bridged by a hydroxide in phosphotriesterase (PTE) employing the nonbonded method and cationic dummy atom that uses virtual atoms to impose orientational requirement for ligands. The was able simulate four‐ligand coordination PTE. distance (3.39 ± 0.07Å) between nearby ions time‐average structure PTE derived from simulation using matched X‐ray (3.31 0.001Å). Unequivocally, fit into experimentally...
To address the problem of acute cocaine overdose, we undertook molecular engineering butyrylcholinesterase (BChE) as a hydrolase so that modest doses could be used to accelerate metabolic clearance this drug. Molecular modeling BChE complexed with suggested inefficient hydrolysis (<i>k</i><sub>cat</sub> = 4 min<sup>−1</sup>) involves rotation toward catalytic triad, hindered by Tyr332. eliminate rotational hindrance and retain substrate affinity, introduced two amino acid substitutions...
Atomic force microscope manipulations of single polysaccharide molecules have recently expanded conformational chemistry to include force-driven transitions between the chair and boat conformers pyranose ring structure. We now expand these observations inversion, a common phenomenon in six-membered molecules. demonstrate that by stretching pectin (1 → 4-linked α- d -galactouronic acid polymer), we could change conformation from then an inverted clearly resolved two-step conversion: 4 C 1 ⇄ ....
The mitochondrial enzyme, dihydrolipoamide dehydrogenase (DLD), is essential for energy metabolism across eukaryotes. Here, conditions known to destabilize the DLD homodimer enabled mouse, pig, or human enzyme function as a protease. A catalytic dyad (S456–E431) buried at interface was identified. Serine protease inhibitors and an S456A E431A point mutation abolished proteolytic activity, whereas other mutations domain enhanced causing partial complete loss of activity. In humans, in have...
Abstract Axonemal dynein ATPases direct ciliary and flagellar beating via adenosine triphosphate (ATP) hydrolysis. The modulatory effect of monophosphate (AMP) diphosphate (ADP) on is not fully understood. Here, we describe a deficiency cilia flagella associated protein 45 ( CFAP45 ) in humans mice that presents motile ciliopathy featuring situs inversus totalis asthenospermia. CFAP45-deficient show normal morphology axonemal ultrastructure. Proteomic profiling links to an module including...