Structural and binding studies of cyclin-dependent kinase 2 with NU6140 inhibitor.

Cyclin-dependent kinase 2 (CDK2) is an established target protein for therapeutic intervention in various diseases, including cancer. Reported inhibitors of CDK2 target the ATP-binding pocket to inhibit the kinase activity. Many small molecule CDK2 inhibitors have been discovered, and their crystal structure with CDK2 or CDK2-cyclin A complex has been published.

Structure of cyclin-dependent kinase 2 (CDK2) in complex with the specific and potent inhibitor CVT-313.

CVT-313 is a potent CDK2 inhibitor that was identified by screening a purine-analogue library and is currently in preclinical studies. Since this molecule has the potential to be developed as a CDK2 inhibitor for cancer therapy, the potency of CVT-313 to bind and stabilize CDK2 was evaluated, together with its ability to inhibit aberrant cell proliferation. CVT-313 increased the melting temperature of CDK2 by 7°C in thermal stabilization studies, thus indicating its protein-stabilizing effect.

Ternary complex formation of AFN-1252 with Acinetobacter baumannii FabI and NADH: Crystallographic and biochemical studies.

Acinetobacter baumannii is an opportunistic Gram-negative bacterial pathogen, associated mostly with hospital-acquired infections. The emergence of drug resistance strains made it necessary to explore new pathways for the development of more effective antibiotics. Enoyl CoA reductase (FabI), a key enzyme in the fatty acid biosynthesis (FAS) pathway, has emerged as a potential target for antibacterial drug development.

The role of hydrophobicity in tuberculosis evolution and pathogenicity.

The evolution of tubercle bacilli parallels a route from environmental Mycobacterium kansasii, through intermediate "Mycobacterium canettii", to the modern Mycobacterium tuberculosis complex. Cell envelope outer membrane lipids change systematically from hydrophilic lipooligosaccharides and phenolic glycolipids to hydrophobic phthiocerol dimycocerosates, di- and pentaacyl trehaloses and sulfoglycolipids. Such lipid changes point to a hydrophobic phenotype for M.

THPP target assignment reveals EchA6 as an essential fatty acid shuttle in mycobacteria.

Phenotypic screens for bactericidal compounds against drug-resistant tuberculosis are beginning to yield novel inhibitors. However, reliable target identification remains challenging. Here, we show that tetrahydropyrazo[1,5-a]pyrimidine-3-carboxamide (THPP) selectively pulls down EchA6 in a stereospecific manner, instead of the previously assigned target Mycobacterium tuberculosis MmpL3.

Mycolic acids: deciphering and targeting the Achilles' heel of the tubercle bacillus.

Mycolic acids are unique long chain fatty acids found in the lipid-rich cell walls of mycobacteria including the tubercle bacillus Mycobacterium tuberculosis. Essential for viability and virulence, enzymes involved in the biosynthesis of mycolic acids represent novel targets for drug development. This is particularly relevant to the impact on global health given the rise of multidrug resistant and extensively drug resistant strains of M.

MKAN27435 is required for the biosynthesis of higher subclasses of lipooligosaccharides in Mycobacterium kansasii.

Lipooligosaccharides are glycolipids found in the cell wall of many mycobacterial species including the opportunistic pathogen Mycobacterium kansasii. The genome of M. kansasii ATCC12478 contains a cluster with genes orthologous to Mycobacterium marinum LOS biosynthesis genes.

Ancient mycobacterial lipids: Key reference biomarkers in charting the evolution of tuberculosis.

Mycobacterium tuberculosis has a cell envelope incorporating a peptidoglycan-linked arabinogalactan esterified by long-chain mycolic acids. A range of "free" lipids are associated with the "bound" mycolic acids, producing an effective envelope outer membrane. The distribution of these lipids is discontinuous among mycobacteria and such lipids have proven potential for biomarker use in tracing the evolution of tuberculosis.

Biochemical and structural characterization of mycobacterial aspartyl-tRNA synthetase AspS, a promising TB drug target.

The human pathogen Mycobacterium tuberculosis is the causative agent of pulmonary tuberculosis (TB), a disease with high worldwide mortality rates. Current treatment programs are under significant threat from multi-drug and extensively-drug resistant strains of M. tuberculosis, and it is essential to identify new inhibitors and their targets.