A5028797169- Microtubule and mitosis dynamics
- Computational Drug Discovery Methods
- Enzyme Structure and Function
- Cancer, Hypoxia, and Metabolism
- Free Radicals and Antioxidants
- Cancer-related Molecular Pathways
- Photosynthetic Processes and Mechanisms
- Cell death mechanisms and regulation
- Peptidase Inhibition and Analysis
- Biochemical and Molecular Research
- Protein Tyrosine Phosphatases
- Bacterial Genetics and Biotechnology
- Pancreatic function and diabetes
- Synthesis and Biological Evaluation
- Chronic Lymphocytic Leukemia Research
- Analytical Chemistry and Chromatography
- Eicosanoids and Hypertension Pharmacology
- Molecular Sensors and Ion Detection
- Protein Structure and Dynamics
- Plant biochemistry and biosynthesis
- Structural and Chemical Analysis of Organic and Inorganic Compounds
- Neuroscience and Neuropharmacology Research
- Neurological Disorders and Treatments
- Protein Degradation and Inhibitors
- Diabetes and associated disorders
Novartis (China)
2024
Qatar University
2022
Sunesis (United States)
2005-2021
Novartis (United States)
2021
Northern University of Malaysia
2017
Oxfam
2017
Third Way
2017
Rockefeller University
2001-2003
Howard Hughes Medical Institute
1997-2003
Brookhaven National Laboratory
2001
We present a common allosteric mechanism for control of inflammatory and apoptotic caspases. Highly specific thiol-containing inhibitors the human caspase-1 were identified by using disulfide trapping, method site-directed small-molecule discovery. These compounds became trapped forming bond with cysteine residue in cavity at dimer interface approximately 15 A away from active site. Mutational structural analysis uncovered linear circuit functional residues that runs one site through into...
Abstract Bruton's tyrosine kinase (BTK), a member of the TEC family kinases, plays crucial role in B‐cell maturation and mast cell activation. Although structures unphosphorylated mouse BTK domain phosphorylated domains human ITK are known, understanding selectivity profiles inhibitors has been hampered by lack availability high resolution, ligand‐bound structure. Here, we report crystal bound to either Dasatinib (BMS‐354825) at 1.9 Å resolution or...
Using cDNA microarrays, we identified StarD4 as a gene whose expression decreased more than 2-fold in the livers of mice fed high-cholesterol diet. cultured 3T3 cells was also sterol-regulated, and known sterol regulatory element binding protein (SREBP)-target genes showed coordinate regulation. The closest homologues to were two other StAR-related lipid transfer (START) proteins named StarD5 StarD6. StarD4, StarD5, StarD6 are 205- 233-aa consisting almost entirely START domains. These three...
The x-ray structure of the mouse cholesterol-regulated START protein 4 (StarD4) has been determined at 2.2-Å resolution, revealing a compact α/β related to domain present in cytoplasmic C-terminal portion human MLN64. volume putative lipid-binding tunnel was estimated 847 Å 3 , which is consistent with binding one cholesterol-size lipid molecule. Comparison tunnel-lining residues StarD4 and MLN64-START permitted identification possible specificity determinants both molecular tunnels....
Lipoprotein lipase (LPL) plays a central role in triglyceride (TG) metabolism. By catalyzing the hydrolysis of TGs present TG-rich lipoproteins (TRLs), LPL facilitates TG utilization and regulates circulating TRL concentrations. Until very recently, structural information for was limited to homology models, presumably due propensity unfold aggregate. coexpressing with soluble variant its accessory protein glycosylphosphatidylinositol-anchored high-density lipoprotein binding 1 (GPIHBP1)...
X-ray structures of two enzymes in the sterol/isoprenoid biosynthesis pathway have been determined a structural genomics pilot study. Mevalonate-5-diphosphate decarboxylase (MDD) is single-domain α/β protein that catalyzes last three sequential ATP-dependent reactions which convert mevalonate to isopentenyl diphosphate. Isopentenyl disphosphate isomerase (IDI) an metalloenzyme interconversion diphosphate and dimethylallyl diphosphate, condense next step toward synthesis sterols host natural...
Uveal melanoma (UM) is the most common primary intraocular malignancy in adult eye. Despite aggressive local management of UM, development metastases with no effective treatment options for metastatic disease. Genetic analysis UM samples reveals presence mutually exclusive activating mutations Gq alpha subunits GNAQ and GNA11. One key downstream targets constitutively active protein kinase C (PKC) signaling pathway. Herein, we describe discovery darovasertib (NVP-LXS196), a potent pan-PKC...
Overexpression of the transcription factor YY1 activates DNA synthesis in differentiated primary human coronary artery smooth muscle cells. retinoblastoma protein together with blocked this effect. In growth-arrested cells, resides a complex protein, but is not detected serum-stimulated S phase cultures, indicating that interaction and cell cycle-regulated. Recombinant directly interacts YY1, destabilizing inhibiting its initiator function vitro. We conclude cells elevation nuclear level...
We have characterized the irs1 and trs1 genes of human cytomegalovirus. The previously identified mRNAs as well their corresponding protein products pIRS1 pTRS1 could be detected during all phases viral replication cycle. proteins were present in nucleus cytoplasm immediate-early early growth cycle but predominantly cytoplasmic late after infection. Although exhibited little transcriptional activation potential on own, both cooperated with IE1 IE2 to enhance expression from a variety...
BACE-1 (beta-site amyloid precursor protein cleaving enzyme), a prominent target in Alzheimer's disease drug discovery efforts, was surveyed using Tethering technology to discover small molecule fragment ligands that bind the enzyme active site. Screens of library >15000 thiol-containing fragments versus panel site cysteine mutants under redox-controlled conditions revealed several novel amine-containing could be selectively captured by subsets tethering sites. For one such hit class,...
The virus-coded proteins pIRS1 and pTRS1 were found associated with purified human cytomegalovirus virions. not degraded when intact virions treated trypsin, which suggests that they are localized inside the viral particle. In transfection experiments modestly activated expression from a reporter plasmid containing major immediate-early promoter but did influence activity of carrying irs1/trs1 promoter. Both reporters by combination or pUL69, is also present in
S. pneumoniae phosphomevalonate kinase (PMK, PMVK, MvaK2; EC 2.7.4.2; 335 residues; predicted molecular mass = 37026.5 Da) is a cytoplasmic enzyme in the mevalonate-dependent isoprenoid biosynthesis pathway.1, 2 The catalyzes transfer of γ-phosphoryl group ATP to phosphate oxygen (R)-5-phosphomevalonate form (R)-5-pyrophosphomevalonate.3 PMK member GHMP superfamily [named for galactokinase (GK), homoserine (HSK), mevalonate (MK), and PMK], which includes at least 19 30%-identical clusters...
Phosphomevalonate kinase catalyzes an essential step in the so-called mevalonate pathway, which appears to be sole pathway for biosynthesis of sterols and other isoprenoids mammals archea. Despite well documented importance this cause prevention human disease that it is biosynthetic root enormous diverse class metabolites, mechanism phosphomevalonate from any organism not yet characterized. The first structure a Streptococcus pneumoniae was solved recently. enzyme exhibits atypical P-loop...
Caspase-1 (Interleukin-1 Converting Enzyme, ICE) is a proinflammatory enzyme that plays pivotal roles in innate immunity and many inflammatory conditions such as periodic fever syndromes gout. Inflammation often mediated by enzymatic activation of interleukin (IL)-1β IL-18. We detected seven naturally occurring human CASP1 variants with different effects on protein structure, expression, activity. Most mutations destabilized the caspase-1 dimer interface revealed crystal structure analysis...
Recruiting, preparing and supporting teachers remain a public concern in many countries, with similar concerns voiced Qatar. Using Systems Theory Framework, this study explored the systems of influence on Qatari teachers' career development within individual, social, environmental-societal contexts. Q methodology was applied, using 40-statement Q-sample. Forty-two participated study, including 27 males 15 females. Results revealed four distinct perspectives minimal consensus, alluding to...
Polo-like kinase 1 (Plk1) is a member of family serine/threonine kinases involved in the regulation cell-cycle progression and cytokinesis an attractive target for development anticancer therapeutics. A zebrafish homolog human Plk1 (hPlk1) domain (KD) was identified that can be expressed large quantities bacteria crystallizes readily, whether wild-type form or as variant containing activating Thr196-->Asp substitution, one space group under similar conditions both absence presence...