A5089293036- Heat shock proteins research
- Antibiotic Resistance in Bacteria
- Bacterial Genetics and Biotechnology
- Bacterial biofilms and quorum sensing
- Protein Structure and Dynamics
- Computational Drug Discovery Methods
- Metal complexes synthesis and properties
- Ferrocene Chemistry and Applications
- Enzyme Structure and Function
- Prion Diseases and Protein Misfolding
- Trace Elements in Health
- Genetics, Aging, and Longevity in Model Organisms
- Biosimilars and Bioanalytical Methods
- Legionella and Acanthamoeba research
- Organometallic Complex Synthesis and Catalysis
- Vibrio bacteria research studies
- Endoplasmic Reticulum Stress and Disease
- Asymmetric Hydrogenation and Catalysis
- DNA and Nucleic Acid Chemistry
- thermodynamics and calorimetric analyses
- Prostate Cancer Treatment and Research
- Inorganic and Organometallic Chemistry
- Antimicrobial Peptides and Activities
- Chemical Synthesis and Analysis
- X-ray Diffraction in Crystallography
William & Mary
2024
Princeton University
2019-2022
University of California, San Francisco
2018-2022
Institute for Neurodegenerative Disorders
2018
Bard College
2013
Pseudomonas aeruginosa is an opportunistic pathogen that causes disease in immunocompromised individuals and with underlying pulmonary disorders. P. virulence controlled by quorum sensing (QS), a bacterial cell-cell communication mechanism underpins transitions between individual group behaviors. In aeruginosa, the PqsE enzyme QS receptor RhlR directly interact to control expression of genes involved virulence. Here, we show three surface-exposed arginine residues on comprise site required...
Pseudomonas aeruginosa is an opportunistic human pathogen that causes fatal infections. There exists urgent need for new antimicrobial agents to combat P. aeruginosa. We conducted a screen molecules bind the virulence-controlling protein PqsE and characterized hit compounds inhibition of enzymatic activity. The binding conformations two inhibitory molecules, BB391 BB393, were identified by crystallography, inhibitor was mimicked substitution residues E182 S285 with tryptophan. Comparison...
Hetero-multinuclear, platinum/ruthenium species were synthesized and tested for their effect on the motility of A549 (nonsmall cell lung) MDA-MB-231 (breast) cancer cells ability to inhibit DNA mobility using gel electrophoresis. It was found that Ru2Pt trinuclear [Na2]{[RuIIICl4(DMSO-S)(-μ-pyz)]2PtIICl2}, AH197, much more efficient at inhibiting than [C3N2H5][RuIIICl4(DMSO-S)(C3N2H4)], NAMI-A, while dinuclear RuPt [K][RuIIICl4(DMSO-S)(-μ-pyz)PtII(DMSO-S)Cl2], IT127, slightly better NAMI-A....
Hsp70 chaperones bind to various protein substrates for folding, trafficking, and degradation. Considerable structural information is available about how prokaryotic (DnaK) binds substrates, but less known mammalian Hsp70s, of which there are 13 isoforms encoded in the human genome. Here, we report interaction between isoform heat shock cognate 71-kDa (Hsc70 or HSPA8) peptides derived from microtubule-associated Tau, linked Alzheimer's disease. For studies, used an Hsc70 construct (called...
Protein–protein interactions (PPIs) are an important category of putative drug targets. Improvements in high-throughput screening (HTS) have significantly accelerated the discovery inhibitors for some categories PPIs. However, methods suitable multiprotein complexes (e.g. those composed three or more different components) been slower to emerge. Here, we explored approach that uses reconstituted (RMPCs). As a model system, chose heat shock protein 70 (Hsp70), which is ATP-dependent molecular...
Pseudomonas aeruginosa is a leading cause of hospital-acquired infections in the United States. PqsE, thioesterase enzyme, vital for virulence P. aeruginosa, making PqsE an attractive target inhibition. Neither substrate nor product catalysis has been identified. A library 550 million DNA-encoded drug-like small molecules was screened those that bind to purified protein. The structures bound were identified by high throughput sequencing attached DNA barcodes. Putative binders with strongest...
Dominant negative mutants are useful tools in chemical biology, but they do not mimic the action of allosteric inhibitors. We show that properly-placed tryptophan residues can sometimes be superior for this purpose.
AH197, a trinuclear Ru(III)/Pt(II) metal complex, is strikingly more effective than the hallmark anticancer drug cisplatin and Ru(III) clinical candidate NAMI-A in its binding to RNA inhibition of primer DNA synthesis. Heteromultinuclear complexes could potentially serve as far better chemotherapeutics mononuclear complexes.
Allosteric inhibitors can be more difficult to optimize without an understanding of how their binding influences the conformational motions target. Here, we used integrated computational and experimental approach probe molecular mechanism allosteric inhibitor heat shock protein 70 (Hsp70). The anticancer compound, MKT-077, is known bind a conserved site in members Hsp70 family, which favors ADP-bound state interferes with protein-protein interaction (PPI) at long range. However, does not...
The opportunistic pathogen Pseudomonas aeruginosa causes antibiotic-resistant, nosocomial infections in immuno-compromised individuals and is a high priority for antimicrobial development. Key to pathogenicity P. are biofilm formation virulence factor production. Both traits controlled by the cell-to-cell communication process called quorum sensing (QS). QS involves synthesis, release, population-wide detection of signal molecules autoinducers. We previously reported that activity RhlR...
Pseudomonas aeruginosa is a human pathogen that relies on quorum sensing to establish infections. The PqsE quorum-sensing protein required for P. virulence factor production and infection. has reported enzymatic function in the biosynthesis of autoinducer called PQS. However, this activity redundant because, absence PqsE, role fulfilled by alternative thioesterases. Rather, drives pathogenic traits via protein-protein interaction with receptor/transcription RhlR, an enhances affinity RhlR...
Abstract Pseudomonas aeruginosa is a human pathogen that poses significant health threat. Pathogenic behaviors of P. are under control the bacterial cell-cell communication system known as quorum sensing (QS). One QS master regulators, RhlR, receptor/transcription factor not only relies on binding its canonical ligand, C4-homoserine lactone (HSL), but additionally requires protein-protein interaction with enzyme, PqsE. We constructed heterologous reporter strains in Escherichia coli allow...
Abstract Castration-resistant prostate cancer (CRPC) is frequently characterized by elevated expression of alternative nuclear receptors able to at least partially maintain the androgen receptor (AR) transcriptional program. These include ARv7, a ligand binding domain (LBD)-deficient, constitutively active splice variant that correlates with poor prognosis, reduced survival, and resistance existing LBD-targeted standard care therapy. As hormone receptor, AR exists in dynamic cycle molecular...
Abstract The opportunistic pathogen Pseudomonas aeruginosa causes antibiotic resistant, nosocomial infections in immuno-compromised individuals, and is a high priority for antimicrobial development. Key to pathogenicity P. are biofilm formation virulence factor production. Both traits controlled by the cell-to-cell communication process called quorum sensing (QS). QS involves synthesis, release, population-wide detection of signal molecules autoinducers. We previously reported that activity...
ABSTRACT Pseudomonas aeruginosa is a human pathogen that relies on quorum sensing to establish infections. The PqsE quorum-sensing protein required for P. virulence factor production and infection. has reported enzymatic function in the biosynthesis of autoinducer called PQS. However, this activity redundant because, absence PqsE, role fulfilled by alternative thioesterases. Rather, drives pathogenic traits via protein-protein interaction with receptor/transcription factor, RhlR, an enhances...