Reviews & Analysis

Formamidopyrimidine residues are damaged purines that retain the same Watson-Crick hydrogen-bonding face found in the parent nucleobase, yet these lesions are mutagenic. Crystallographic evidence suggests molecular mechanisms by which these lesions 'mispair' to generate mutations during DNA replication.

Elusive pan-phosphohistidine (pHis) antibodies have been generated using a hydrolytically stable triazolyl-phosphonate hapten, promising to substantially accelerate efforts to better understand the role of pHis in biology.

BCL-X_L and other anti-apoptotic BCL-2 family proteins serve as guardians of cellular survival. A new selective small-molecule inhibitor of BCL-X_L is developed to promote apoptosis in cancers that are addicted to BCL-X_L.

NMR analysis of the conformational energy landscape of the catabolite activator protein suggests that allosteric inhibition can be achieved by blocking access to elusive high-energy states of proteins.

A study of an insect prenyltransferase demonstrates that the product specificity of this bifunctional enzyme can be regulated by the presence of different divalent metal cofactors, resulting, for example, in the production of the precursors for either insect defense compounds or developmental hormones.

Metabolic aberrations affecting protein and DNA methylation are a potential source of cancer. A new study shows that the metabolic enzyme nicotinamide N-methyl-transferase, which is overexpressed in several types of tumors, can enhance cancer aggressiveness by draining methyl groups from S-adenosyl-methionine.

Pseudomonas aeruginosa uses several intertwined cell-cell communication systems, called quorum sensing (QS) systems, to control gene expression. A QS signal–dependent transcription factor called LasR is at the top of the network. Mutations in lasR inactivate QS, but a new study has revealed an alternate signaling pathway that allows Pseudomonas aeruginosa to bypass LasR and activate a subset of quorum-controlled genes in times of stress.

The synergistic action of cellulases is critical for the effective saccharification of cellulosic biomass, but the details of this cooperation remain poorly understood. Quantitative analysis at the level of single molecules now unveils a form of 'work sharing' among cellulolytic enzymes based on different adsorption specificities of their carbohydrate-binding modules.

Proteins can self-assemble into functional states, or they can end up as aberrant and sometimes toxic aggregates. Metastable intermediate states are often detected in these processes, and their structural characterization provides vital information about the balance between functional and pathological behavior in living systems.

The structure of a bacterial methane oxidation complex reveals how protein-protein interactions can mediate coupling of proton, electron and substrate delivery to a metal active site.

A small molecule called optovin acts as a light-sensitive ligand for an ion channel involved in the detection of painful sensory stimuli. This unexpected finding emerged from a behavioral screen in zebrafish and provides a tool for the remote control of pain by light.

Secreted Hedgehog (Hh) proteins are essential in development, and their aberrant activity contributes to certain cancers. Chemically targeting a lipid modification of Hh proteins results in loss of their cellular activity, revealing new strategies for cancer intervention and elucidation of the role of lipids in signal transduction.

Physiologically relevant ligands for mammalian odorant receptors have been elusive. A mouse odorant receptor–based bioassay has now been used to guide purification and identification of a natural ligand that mediates attraction of female mice to male urine.

Control of protein self-assembly and disassembly, which is central to metabolism and engineering applications, remains challenging. Here, a perspicacious redesign of interfaces in the multisubunit ferritin protein cage provides single, modifiable subunits that assemble with Cu²⁺ templating and give insights into the cage assembly code.

PUMA is a BCL-2 family protein that transmits stress signals to promote apoptosis. Upon DNA damage, a unique binding determinant within PUMA triggers partial unfolding of BCL-X_L, resulting in the release of sequestered p53 and commitment to p53-dependent cell death.

There is a considerable amount of oxidized glutathione in living cells, yet it is virtually absent from the cytosol. The mystery of where it resides has now been solved. A study in baker's yeast revealed that oxidized glutathione is selectively stashed in vacuoles.

Cholic acid and 24(S),25-epoxycholesterol are oxysterols detected in the developing mesencephalic tissue and selectively regulate the production of either the red nucleus or dopaminergic neurons via activation of the liver X receptors.

Whole-organism screening is emerging as a promising alternative to cell-based assays, particularly for the study of processes that integrate information across cells and tissues. High-throughput screening of zebrafish larvae has enabled the discovery of small molecules that lower blood glucose levels and alleviate pathological symptoms in a mouse model of obesity and diabetes.