Primary resistance in Candida albicans to flucytosine (5-FC) was investigated 25 strains by identifying and sequencing the genes FCA1, FUR1, FCY21, FCY22, which code for cytosine deaminase, uracil phosphoribosyltransferase (UPRT), two purine-cytosine permeases, respectively. These proteins are involved pyrimidine salvage 5-FC metabolism. An association between a polymorphic nucleotide found within FUR1 where substitution of cytidylate thymidylate at position 301 results replacement arginine...

The resistance of tissues to physical stress is dependent upon strong cell-cell adhesion in which desmosomes play a crucial role. We propose that fulfil this function by adopting more strongly adhesive state, hyper-adhesion, than other junctions. show the hyper-adhesive epidermis resist disruption ethylene glycol bis(2-aminoethyl ether)-N,N,N'N'-tetraacetic acid (EGTA) and are thus independent Ca2+. Ca2+ independence normal condition for tissue desmosomes. associated with an organised...

Differentiation in African trypanosomes (Trypanosoma brucei) entails passage between a mammalian host, where parasites exist as proliferative slender form or G0-arrested stumpy form, and the tsetse fly. Stumpy forms arise at peak of each parasitaemia are committed to differentiation procyclic that inhabit midgut. We have identified protein tyrosine phosphatase (TbPTP1) inhibits trypanosome differentiation. Consistent with phosphatase, recombinant TbPTP1 exhibits anticipated substrate...

The genomes of the three parasitic protozoa Trypanosoma cruzi, brucei and Leishmania major are main subject this study. These parasites responsible for devastating human diseases known as Chagas disease, African sleeping sickness cutaneous Leishmaniasis, respectively, that affect millions people in developing world. prevalence these neglected results from a combination poverty, inadequate prevention difficult treatment. Protein phosphorylation is an important mechanism controlling...

Bacterial pathogens have developed sophisticated mechanisms of evading the immune system to survive in infected host cells. Central pathogenesis Mycobacterium tuberculosis is arrest phagosome maturation, partly through interference with PtdIns signalling. The protein phosphatase MptpB an essential secreted virulence factor M. tuberculosis. A combination bioinformatics analysis, enzyme kinetics and substrate-specificity characterization revealed that exhibits both dual-specificity activity...

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTMolecular structure of the A-tract DNA dodecamer d(CGCAAATTTGCG) complexed with minor groove binding drug netropsinLydia Tabernero, Nuria Verdaguer, Miquel Coll, Ignasi Fita, Gijs A. van der Marel, Jacques H. Boom, Alexander Rich, and Joan AymamiCite this: Biochemistry 1993, 32, 33, 8403–8410Publication Date (Print):August 24, 1993Publication History Published online1 May 2002Published inissue 24 August...

The secreted Mycobacterium tuberculosis protein tyrosine phosphatase (MptpB) is a virulence factor for M. and contributes to its survival within host macrophages. aim of this study was identify potent selective inhibitors MptpB determine the efficacy these compounds in mycobacterium-infected inhibitory effect small library on first examined vitro. further We have identified new family double-site isoxazole-based that are MptpB. Importantly, substantially reduce mycobacterial infected In...

Desmosomes and adherens junctions are cadherin-based protein complexes responsible for cell-cell adhesion of epithelial cells. Type 1 cadherins show specific homophilic that plays a major role in developmental tissue segregation. The desmosomal cadherins, desmocollin desmoglein, occur as several different isoforms with overlapping expression some tissues where located the same desmosomes. Although adhesive binding has been investigated variety ways, their interaction desmosome-forming cells...

3-hydroxy-3-methylglutaryl–CoA (HMG-CoA) reductase is the rate-limiting enzyme and first committed step in biosynthesis of cholesterol mammals. We have determined crystal structures two nonproductive ternary complexes HMG-CoA reductase, HMG-CoA/NAD + mevalonate/NADH, at 2.8 Å resolution. In structure Pseudomonas mevalonii apoenzyme, last 50 residues C terminus (the flap domain), including catalytic residue His381, were not visible. The reported here reveal a substrate-induced closing domain...

Chromosomal instability can result from defective control of checkpoints and is associated with malignant cell growth. Monopolar spindle 1 (Mps1) a dual-specificity protein kinase that has important roles in the prevention aneuploidy during cycle might therefore be potential target for new therapeutic agents treatment cancer. To gain insights into molecular mechanism Mps1 inhibition by small molecules, we determined x-ray structure Mps1, both alone complex ATP-competitive inhibitor SP600125....

Significance We present here an entirely novel concept in the field of cell–cell adhesion, whereby flexibility extracellular domains cadherin molecules determines characteristics and behavior intercellular junctions. The structure ectodomain desmosomal desmoglein 2 shows it is flexible its calcium-bound form. This ectodomains may be key facilitating a unique property desmosomes: ability to switch from strong calcium-independent hyperadhesion adult tissues weaker calcium-dependent adhesion wounds.

Mycobacterium tuberculosis protein-tyrosine-phosphatase B (MptpB) is a secreted virulence factor that subverts antimicrobial activity in the host. We report here structure-based design of selective MptpB inhibitors reduce survival multidrug-resistant strains macrophages and enhance killing efficacy by first-line antibiotics. Monotherapy with an orally bioavailable inhibitor reduces infection burden acute chronic guinea pig models improves overall pathology. Our findings provide new paradigm...

Abstract Motivation: The classification of proteins expressed by an organism is important step in understanding the molecular biology that organism. Traditionally, this has been performed human experts. Human knowledge can recognise functional properties are sufficient to place individual gene product into a particular protein family group. Automation task usually fails meet ‘gold standard’ annotator because difficult recognition stage. growing number genomes, rapid changes and central role...

Low-molecular weight protein tyrosine phosphatases are virtually ubiquitous, which implies that they have important cellular functions. We present here the 2.2 Å resolution X-ray crystallographic structure of wild-type LTP1, a low-molecular phosphatase from Saccharomyces cerevisiae. also an inactive mutant substrate complex LTP1 with p-nitrophenyl phosphate (pNPP) at 1.7 Å. The crystal structures and both two molecules per asymmetric unit. was grown in HEPES buffer, sulfonate anion resembles...

Fungal pathogens are responsible for millions of life-threatening infections on an annual basis worldwide. The current repertoire antifungal drugs is very limited and, worryingly, resistance has emerged and already become a serious threat to our capacity treat fungal diseases. first step develop new often identify molecular targets in the pathogen whose inhibition during infection can prevent its growth. However, models not suitable validate established infections. Here, we have...

Sulfur metabolism is an essential aspect of fungal physiology and pathogenicity. Fungal sulfur comprises anabolic catabolic routes that are not well conserved in mammals, therefore considered a promising source prospective novel antifungal targets. To gain insight into Aspergillus fumigatus sulfur-related during infection, we used NanoString custom nCounter-TagSet compared the expression 68 key metabolic genes different murine models invasive pulmonary aspergillosis, at 3 time-points, under...

Hydroxymethylglutaryl-CoA (HMG-CoA) reductase is the primary target in current clinical treatment of hypercholesterolemias with specific inhibitors "statin" family. Statins are excellent class I (human) enzyme but relatively poor II enzymes important bacterial pathogens. To investigate molecular basis for this difference we determined x-ray structure Pseudomonas mevalonii HMG-CoA complex statin drug lovastatin. The shows lovastatin bound active site and its interactions residues critically...

The dual-specificity protein kinase monopolar spindle 1 (Mps1) is a central component of the mitotic assembly checkpoint (SAC), sensing mechanism that prevents anaphase until all chromosomes are bioriented on metaphase plate. Partial depletion Mps1 levels sensitizes transformed, but not untransformed, human cells to therapeutic doses anticancer agent Taxol, making it an attractive novel cancer target. We have previously determined X-ray structure catalytic domain in complex with...

ESCRT-I is essential for the multivesicular body (MVB) sorting of ubiquitinated cargo such as epidermal growth factor receptor, well divergent cellular functions cell division and retroviral budding. has four subunits; TSG101, VPS28, VPS37 MVB12. There are several members MVB12 families in mammalian cells, their differential incorporation into could provide function-specific variants complex. However, it remains unclear whether these different forms combine randomly or generate selective...