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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.
A histone deacetylase inhibitor seems to restore the transcriptional activity of a silenced gene by overcoming heterochromatin effects, thereby offering a potential treatment for the neurodegenerative disease Friedreich's ataxia.
D-Amino acids can be useful building blocks for pharmaceuticals, but synthesizing them at a low cost remains challenging. A good catalyst for generating unnatural D-amino acids has been created by expanding the substrate range of a highly specific dehydrogenase.
Enzymatic cyclization of the linear polyketide chain to form a macrolactone is a key step in the biosynthesis of type I polyketide natural products. Structural biology and inhibitor design were used to gain insight into the mechanism and specificity of this enzymatic process.
Caspase-3 is a central player in the orchestration of apoptotic cell death. A newly identified compound selectively activates caspase-3, has proapoptotic activity against transformed cells and retards the growth of procaspase-3–rich tumors.
New advances in mass spectrometry allow researchers to determine the way multiple protein subunits are assembled spatially. This approach can reveal topology and provide information on the interacting proteins of the 19S proteasome.
Nitrite is an inorganic anion essential in cell signaling and vascular biology. A new study shows that the multicopper oxidase ceruloplasmin is critical for maintaining plasma nitrite, revealing a new link between copper and nitric oxide homeostasis.
Differentiation-inducing factor 1 is a modified polyketide natural product involved in the differentiation of Dictyostelium discoideum cells. A new study shows that a type III polyketide synthase existing in an unusual association with type I fatty acid synthase domains is responsible for biosynthesis of this signaling compound.
Glycosaminoglycan-protein interactions are an important frontier for discovering new mechanisms of cellular regulation by complex sugars. The integration of the 'chemical glycomics' strategies of synthetic chemistry, arrays and biological assays shows that the precise pattern of sugar sulfation dictates the specificity of a sugar's function.
Endogenous electric fields in wounds have been documented for centuries, but they have received little attention from the scientific community. A new study shows that manipulation of these electric fields affects wound healing in vivo and identifies the phosphoinositide 3-kinase signaling pathway as a key component of cell migration in response to electric cues.
