A5072955695- SARS-CoV-2 and COVID-19 Research
- Computational Drug Discovery Methods
- Cancer, Hypoxia, and Metabolism
- Pancreatic function and diabetes
- Diet, Metabolism, and Disease
- Biochemical and Molecular Research
- Folate and B Vitamins Research
- Calcium signaling and nucleotide metabolism
- bioluminescence and chemiluminescence research
- X-ray Diffraction in Crystallography
- PARP inhibition in cancer therapy
- Cancer therapeutics and mechanisms
- Metabolism, Diabetes, and Cancer
- Crystallization and Solubility Studies
- Enzyme Structure and Function
- Erythrocyte Function and Pathophysiology
- Cystic Fibrosis Research Advances
- Crystallography and molecular interactions
- Various Chemistry Research Topics
- Neurological Disorders and Treatments
- thermodynamics and calorimetric analyses
- RNA modifications and cancer
- Photoreceptor and optogenetics research
- RNA and protein synthesis mechanisms
- vaccines and immunoinformatics approaches
New York University Abu Dhabi
2014-2024
New York University
2017-2023
McGill University
2010-2012
University of Toronto
2007-2010
Structural Genomics Consortium
2007-2010
University of Oklahoma
2004-2008
Therapeutic efforts to restore biosynthetic processing of the cystic fibrosis transmembrane conductance regulator lacking F508 residue (DeltaF508CFTR) are hampered by ubiquitin-dependent lysosomal degradation nonnative, rescued DeltaF508CFTR from plasma membrane. Here, functional small interfering RNA screens revealed contribution chaperones, cochaperones, and ubiquitin-conjugating -ligating enzymes elimination unfolded CFTR cell surface, as part a peripheral protein quality-control system....
Coronaviruses are responsible for multiple pandemics and millions of deaths globally, including the current pandemic coronavirus disease 2019 (COVID-19). Development antivirals against coronaviruses, severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) COVID-19, is essential containing future outbreaks. SARS-CoV-2 proteases represent important targets development because their role in processing viral polyproteins. 3-Chymotrypsin-like protease (3CLpro) one such protease. The cleavage...
The eukaryotic nicotinamide riboside kinase (Nrk) pathway, which is induced in response to nerve damage and promotes replicative life span yeast, converts adenine dinucleotide (NAD+) by phosphorylation adenylylation. Crystal structures of human Nrk1 bound nucleoside nucleotide substrates products revealed an enzyme structurally similar Rossmann fold metabolite kinases allowed the identification active site residues, were shown be essential for Nrk2 activity vivo. Although account 500-fold...
3C-like protease (3CLpro) processes and liberates functional viral proteins essential for the maturation infectivity of severe acute respiratory syndrome coronavirus 2, virus responsible COVID-19. It has been suggested that 3CLpro is catalytically active as a dimer, making dimerization interface target antiviral development. Guided by structural analysis, here we introduced single amino acid substitutions at nine residues three key sites dimer to assess their impact on activity. We show site...
Small heat shock proteins (sHsps) bind destabilized during cell stress and disease, but their physiological functions are less clear. We evaluated the impact of Hsp27, an sHsp expressed in airway epithelial cells, on common protein misfolding mutant that is responsible for most cystic fibrosis. F508del fibrosis transmembrane conductance regulator (CFTR), a well-studied subject to cytosolic quality control, selectively associated with whose overexpression preferentially targeted CFTR...
Overexpression of mitochondria-bound hexokinase II (HKII) in cancer cells plays an important role their metabolic reprogramming and protects them against apoptosis, thereby facilitating growth proliferation. Here, we show that covalently coupling a peptide corresponding to the mitochondrial membrane–binding N-terminal 15 aa HKII (pHK) short, penetration-accelerating sequence (PAS) enhances cellular uptake, localization, cytotoxicity HeLa cells. Further analysis revealed pHK-PAS depolarized...
The high proliferation rate of tumor cells demands energy and metabolites that are sustained by a glycolytic flux known as the 'Warburg effect'. activation further metabolism glucose is initiated hexokinase, focal point metabolic regulation. human hexokinase 2 (HK2) overexpressed in all aggressive tumors predominantly found on outer mitochondrial membrane, where interactions through its N-terminus initiates maintains tumorigenesis. Here, we report structure HK2 complex with...
Pantothenate kinase (PanK) catalyzes the first step in CoA biosynthesis and there are three human genes that express four isoforms with highly conserved catalytic core domains. Here we report homodimeric structures of cores PanK1alpha PanK3 complex acetyl-CoA, a feedback inhibitor. Each monomer adopts fold actin superfamily inhibitor-bound explain basis for allosteric regulation by thioesters. These also provide an opportunity to investigate structural effects PanK2 mutations have been...
The main protease of SARS-CoV-2, 3-chymotrypsin-like (3CLpro), is a prominent target for antiviral development due to its essential role in the viral life cycle. Research has largely focused on competitive inhibitors 3CLpro that active site. However, allosteric sites distal peptide substrate-binding region are also potential targets design reversible noncompetitive inhibitors. Computational analyses have examined importance key contacts at 3CLpro, but these not been validated experimentally....
Background Hexokinases (HKs) catalyze the first step in glucose metabolism. Of three mammalian 100-kDa HK isoforms, HKI and II can bind to mitochondria protect against cell death. HKIII does not mitochondria, little is known about its regulation or cytoprotective effects. We studied of at transcriptional protein levels investigated role cellular protection. Methodology/Principal Findings show that like HKII, expression regulated by hypoxia, but other factors regulate HKII have no effect on...
O-Acetylserine sulfhydrylase is a pyridoxal 5'-phosphate-dependent enzyme that catalyzes the final step in cysteine biosynthetic pathway enteric bacteria and plants, replacement of β-acetoxy group O-acetyl-l-serine by thiol to give l-cysteine. Two isozymes are found Salmonella typhimurium, with A-isozyme expressed under aerobic B-isozyme anaerobic conditions. The structure O-acetylserine B has been solved 2.3 Å exhibits overall fold very similar A-isozyme. main difference between two more...
Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is responsible for the novel coronavirus disease 2019 (COVID-19). An appealing antiviral drug target 3C-like protease (3CLpro) that processing of viral polyproteins and liberation functional proteins essential maturation infectivity virus. In this study, multiple thermal analytical techniques have been implemented to acquire thermodynamic parameters 3CLpro at different buffer conditions. exhibited relatively high stabilities over a...
We have previously reported an increased expression of cytokeratins 8/18 (K8/K18) in cells expressing the F508del mutation cystic fibrosis transmembrane conductance regulator (CFTR). This is associated with colocalization CFTR and K18 vicinity endoplasmic reticulum, although this reversed by treating curcumin, resulting rescue F508del-CFTR. In present work, we hypothesized that (i) K8/K18 network may interact physically CFTR, (ii) interaction modify function. was immunoprecipitated from HeLa...
There are many methods that can be used to incorporate concepts of crystallography into the learning experiences students, whether they in elementary school, at university or part public large. It is not always critical those who teach have immediate access diffraction equipment able introduce symmetry, packing molecular structure an age- and audience-appropriate manner. Crystallography as a tool for teaching general chemistry well research techniques without ever having student determine...
The different colors of light emitted by bioluminescent beetles that use an identical substrate and chemiexcitation reaction sequence to generate remain a challenging controversial mechanistic conundrum. crystal structures two beetle luciferases with red- blue-shifted relative the green yellow common firefly species provide direct insight into molecular origin bioluminescence color. structure green-emitting luciferase from Amydetes vivianii is monomeric structural fold similar previously...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for disease 2019 (COVID-19), one of the most challenging global pandemics modern era. Potential treatment strategies against COVID-19 are yet to be devised. It crucial that antivirals interfere with SARS-CoV-2 life cycle identified and developed. 3-Chymotrypsin-like protease (3CLpro) an attractive antiviral drug target SARS-CoV-2, coronaviruses in general, because its role processing viral polyproteins. Inhibitors...
Coronaviruses have been responsible for multiple challenging global pandemics, including coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome 2 (SARS-CoV-2). Papain-like protease (PLpro), one of two cysteine proteases the maturation and infectivity SARS-CoV-2, processes liberates functional proteins from viral polyproteins cleaves ubiquitin ISG15 modifications to inhibit innate immune sensing. Consequently, PLpro an attractive target developing COVID-19...
The first structure determination of a neuraminidase inhibitor, oseltamivir phosphate, the active component anti-influenza agent Tamiflu, was achieved by single crystal X-ray diffraction with synchrotron radiation. reproduces to great extent binding inhibitor in site and provides more accurate structural parameters as well detailed insight into preferences inhibitor.
Hexokinase (HK) catalyzes the first step in glucose metabolism, making it an exciting target for inhibition of tumor initiation and progression due to their elevated metabolism. The upregulation hexokinase-2 (HK2) many cancers its limited expression normal tissues make a particularly attractive selective cancer growth eradication tumors with side effects. design such safe effective anticancer therapeutics requires development HK2-specific inhibitors that will not interfere other HK isozymes....
Excessive fructose consumption is a primary contributor to the global surges in obesity, cancer, and metabolic syndrome. Fructolysis not robustly regulated initiated by ketohexokinase (KHK). In this study, we determined crystal structure of KHK-A, one two human isozymes KHK, apo-state at 1.85 Å resolution, investigated roles residues fructose-binding pocket mutational analysis. Introducing alanine D15, N42, or N45 inactivated whereas mutating R141 K174 reduced activity thermodynamic...