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Drug design for voltage-gated ion channels has long been hampered by the absence of crystal structures and the challenge of achieving subtype selectivity. A combination of mutagenesis, electrophysiology and molecular modeling has led to the identification of a new side pocket binding site for the small molecule Psora-4 between the pore and the voltage-sensor domain of Kv1.5, offering opportunities to design allosteric ion channel modulators.
Mass spectrometry advances in single-cell metabolomics enable the discovery of a new biological insight that is not accessible from population-level studies. A new study reveals that single baker's yeast cells provide sufficient material to study chemical and genetic inhibition of glycolysis and identifies metabolic subpopulations that would be invisible in bulk.
Bioorthogonal chemistry, facilitated by enzymatic incorporation of chemical reporters in vitro or in cells, permits selective labeling and visualization of proteins, nucleic acids and other biomolecules such as glycans and lipids and facilitates the interrogation of their cellular functions.
Integration of chemistry-based approaches into enzyme engineering provides a versatile strategy for biocatalyst development with the potential for improved performance and new catalytic activities. Application of this strategy led to the development of a whole-cell catalyst capable of converting olefins into cyclopropanes, synthetic intermediates used in the synthesis of more functionalized cycloalkanes and acyclic compounds.
Transduction of extracellular signals by cilia requires regulated entry of pathway components. A new study uses chemical dimerization to induce diffusion and identifies size-dependent soluble diffusion rates consistent with a sieve-like barrier with 8-nm pore radii at the ciliary base.
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-XL and other anti-apoptotic BCL-2 family proteins serve as guardians of cellular survival. A new selective small-molecule inhibitor of BCL-XL is developed to promote apoptosis in cancers that are addicted to BCL-XL.
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.
