Articles in 2013

Compounds that restore function to the cystic fibrosis–linked ΔF508 allele of CFTR can be classified on the basis of three corrector functions, representing different targets within the five domains of the channel protein. Combinations of individual compounds in the three classes can restore considerable function to the mutant channel.

Chemically inducible diffusion trap at cilia (CIDTc), a method to trap proteins in the cilia, was applied to study the kinetics of protein accumulation and reveal a molecular sieve at the ciliary base. CIDTc can also be applied to study signaling pathways in the cilia.

Advanced NMR studies of catabolite activator protein show that allosteric inhibitors can prevent conformational changes needed for a protein to bind its ligand, offering an explanation for why these inhibitors may not appear to cause any effect when monitored using static techniques.

The radical SAM enzyme Cfr catalyzes methylation of a ribosomal adenosine, causing broad antibiotic resistance. EPR and ENDOR techniques now provide direct evidence for the proposed enzymatic mechanism by detecting a central crosslinked intermediate in which a radical is located on the nucleotide.

N-linked glycosylation in archaea has generally been assumed to follow the logic determined for bacterial and eukaryotic pathways. Biochemical investigations of the process in Methanococcus voltae now allow the functional assignment of three enzymes that generate and use an unusual monophosphate intermediate, drawing distinctions between domains of life.

DNA origami has shown that principles of molecular recognition can be used to reshape biomolecules into nonphysiological forms. The design and synthesis of a continuous, 12-helix polypeptide that spontaneously self-assembles into a defined tetrahedron now demonstrates that protein structures can be similarly manipulated.

A small molecule that protects macrophages from lethal toxin–induced pyroptosis reveals a kinase-independent role for protein kinase R in caspase-1 activation.

A high-throughput chemical screen followed by structure-guided chemical design leads to the first potent and selective small-molecule BCL-X_L inhibitor.

Structure-based design of RARα antagonists leads to compounds that can selectively upregulate chaperone-mediated autophagy (CMA), yielding the first chemically tractable target for regulating CMA in cells.

The 20° tilt angle of β-strands within the transmembrane β-barrel formed by bacterial perfingolysin O reveals how helices in adjacent monomers select the proper hydrogen-bonding partner during assembly.

The use of PALM imaging to quantify enzyme localization on technically challenging heterogeneous substrates yields a new directionally dependent metric for describing substrate specificity, the application of which explains synergy between carbohydrate-binding domains from diverse cellulases.

IQS is a Pseudomonas aeruginosa quorum sensing molecule that functions during phosphate limitation and lies near the top of the QS signaling hierarchy.

Methylthiolation by radical SAM enzymes is thought to include the sacrificial breakdown of a second Fe-S cluster to generate the sulfur cosubstrate. A biochemical, spectroscopic and structural study of two methylthiotransferases shows these enzymes retain their clusters, using exogenous thiols to modify their targets.

Constrained ligands activate a canonical ER pathway via a common structural mechanism, whereas dynamic ligands rewire the canonical pathway; DBD-dependent activity interferes with canonical ER proliferative signals and associates with a strong anti-inflammatory effect.

Class IIa histone deacetylases (HDACs) are generally viewed as noncatalytic readers of acetylated lysines within proteins. Specific inhibitors of class IIa HDACs, based on a new zinc-binding scaffold, offer chemical probes to explore the biological function and potential druggability of this enzyme subclass.

ATP-competitive inhibitors compete with the Hsp90 cochaperone Cdc37 for the ATP site in kinases, depriving kinases of access to protein quality control machinery and promoting their degradation. Thus, in addition to inhibiting the catalytic activity of kinases, ATP-competitive inhibitors can reduce the number of active kinases in a cell by promoting their degradation.

Proteins that sample multiple conformations in the absence of a ligand have been presumed to operate via a conformational selection mechanism. Single molecule FRET studies of maltose binding protein now cast doubts on that assumption.

NNMT converts SAM to the stable metabolite 1-methylnicotinamide, which reduces the methylation potential of cancer cells and thereby alters their epigenetic state to heighten the expression of protumorigenic genes.

A new small-molecule inhibitor that selectively binds an internal cavity in HIF-2α allosterically disrupts HIF-2α–ARNT interaction in vitro and in cells. This compound should allow scientists to interrogate HIF-2α's activity in hypoxia and cancer cells.

One pathway for lysine biosynthesis uses a carrier protein, LysW, to protect the substrate. LysW is now shown to mediate entry of a second substrate into the same metabolic pathway, with structural and biochemical evidence identifying an amino acid motif that determines substrate specificity.