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See detailLYP inhibits T-cell activation when dissociated from CSK
Vang; Liu, Wallace H; Delacroix, Laurence ULg et al

in Nature Chemical Biology (2012)

Lymphoid tyrosine phosphatase (LYP) and C-terminal Src kinase (CSK) are negative regulators of signaling mediated through the T-cell antigen receptor (TCR) and are thought to act in a cooperative manner ... [more ▼]

Lymphoid tyrosine phosphatase (LYP) and C-terminal Src kinase (CSK) are negative regulators of signaling mediated through the T-cell antigen receptor (TCR) and are thought to act in a cooperative manner when forming a complex. Here we studied the spatiotemporal dynamics of the LYP–CSK complex in T cells. We demonstrate that dissociation of this complex is necessary for recruitment of LYP to the plasma membrane, where it downmodulates TCR signaling. Development of a potent and selective chemical probe of LYP confirmed that LYP inhibits T-cell activation when removed from CSK. Our findings may explain the reduced TCR-mediated signaling associated with a single-nucleotide polymorphism that confers increased risk for certain autoimmune diseases, including type 1 diabetes and rheumatoid arthritis, and results in expression of a mutant LYP that is unable to bind CSK. Our compound also represents a starting point for the development of a LYP-based treatment of autoimmunity. [less ▲]

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See detailStructural and mechanistic basis of penicillin-binding protein inhibition by lactivicins
Macheboeuf, Pauline; Fischer, Delphine S; Brown, Tom Jr et al

in Nature Chemical Biology (2007), 3(9), 565-569

beta-lactam antibiotics, including penicillins and cephalosporins, inhibit penicillin-binding proteins (PBPs), which are essential for bacterial cell wall biogenesis. Pathogenic bacteria have evolved ... [more ▼]

beta-lactam antibiotics, including penicillins and cephalosporins, inhibit penicillin-binding proteins (PBPs), which are essential for bacterial cell wall biogenesis. Pathogenic bacteria have evolved efficient antibiotic resistance mechanisms that, in Gram-positive bacteria, include mutations to PBPs that enable them to avoid beta-lactam inhibition(1). Lactivicin (LTV; 1) contains separate cycloserine and c-lactone rings and is the only known natural PBP inhibitor that does not contain a beta-lactam(2-4). Here we show that LTV and a more potent analog, phenoxyacetyl-LTV (PLTV; 2), are active against clinically isolated, penicillin-resistant Streptococcus pneumoniae strains. Crystallographic analyses of S. pneumoniae PBP1b reveal that LTV and PLTV inhibition involves opening of both monocyclic cycloserine and gamma-lactone rings. In PBP1b complexes, the ring-derived atoms from LTV and PLTV show a notable structural convergence with those derived from a complexed cephalosporin (cefotaxime; 3). The structures imply that derivatives of LTV will be useful in the search for new antibiotics with activity against beta-lactam-resistant bacteria. [less ▲]

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See detailAt the crossroad of thiamine degradation and biosynthesis
Bettendorff, Lucien ULg

in Nature Chemical Biology (2007), 3(8), 454-455

The physiological significance of thiaminase II has escaped our understanding for many years. The recent discovery of a new thiamine salvage pathway shows that this enzyme is involved in the regeneration ... [more ▼]

The physiological significance of thiaminase II has escaped our understanding for many years. The recent discovery of a new thiamine salvage pathway shows that this enzyme is involved in the regeneration of precursors for thiamine biosynthesis. [less ▲]

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See detailDiscovery of a natural thiamine adenine nucleotide
Bettendorff, Lucien ULg; Wirtzfeld, Barbara; Makarchikov, Alexander F et al

in Nature Chemical Biology (2007), 3(4), 211-212

Several important cofactors are adenine nucleotides with a vitamin as the catalytic moiety. Here, we report the discovery of the first adenine nucleotide containing vitamin B1: adenosine thiamine ... [more ▼]

Several important cofactors are adenine nucleotides with a vitamin as the catalytic moiety. Here, we report the discovery of the first adenine nucleotide containing vitamin B1: adenosine thiamine triphosphate (AThTP, 1), or thiaminylated ATP. We discovered AThTP in Escherichia coli and found that it accumulates specifically in response to carbon starvation, thereby acting as a signal rather than a cofactor. We detected smaller amounts in yeast and in plant and animal tissues. [less ▲]

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