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Fragment-based drug design capitalizes on the modular binding of low-molecular-weight, low-affinity ligands. However, the deconstruction of lead-like inhibitors into putative fragments reveals the surprising complexity of dealing with low-affinity leads, thereby challenging oversimplification of these leads and highlighting the richness of their chemical diversity and molecular recognition.
Ascidians obtain diverse libraries of cytotoxic compounds by maintaining cyanobacterial symbionts that have combinatorial variants of a natural-product pathway. The biosynthetic flexibility of this route can be used to genetically engineer new substances.
Chemically synthesizing complex oligosaccharides remains a significant challenge. Through the addition of hydrophobic appendages to 'unnatural' substrates, some oligosaccharide-forming glycosyltransferases can direct the formation of distinct sugar linkages while maintaining stereoselectivity.
The sheer quantity and complexity of gene expression data can provide extraordinarily accurate descriptions of differences between states of cells, tissues and whole organisms. A compendium of genomic signatures that attempts to describe all biological states has the potential to reveal hidden connections among drugs, genes and diseases.
Understanding how cytokines interact with multimeric cell receptors to generate signals governing cell behavioral responses is crucial for the development of these promising pharmacological agents. A powerful quantitative approach is reported that was used to analyze the complicated case of binding of the GDNF family member artemin to the heteromeric GFRα3-Ret receptor.
A new pathway involving a fatty acid intermediate for the initiation of membrane phospholipid synthesis has been identified. This finding answers the question of how most bacteria catalyze the first acylation step in phosphatidic acid formation.
Accumulating evidence indicates that protein S-nitrosylation may convey a broad spectrum of cellular signals. S-nitrosylation of critical cysteine thiols activates a subset of cation-permeable, transient receptor potential channel proteins (TRPs), which may represent a general mechanism for regulating stimulus-coupled cellular Ca2+ flux.
Ion-channel gating, or stochastic fluctuation between an open and a closed state, is not fully understood at the atomic level. Analysis of the bacterial channel OmpA now suggests that one mode of gating depends on the switching of a salt bridge within the pore.
