Volume 11 Issue 11, November 2015

A 'chemical biology of cellular membranes' must capture the way that mesoscale perturbations tune the biochemical properties of constituent lipid and protein molecules and vice versa. Whereas the classical paradigm focuses on chemical composition, dynamic modulation of the physical shape or curvature of a membrane is emerging as a complementary and synergistic modus operandi for regulating cellular membrane biology.

We asked a collection of chemical biologists: “What advice would you give to a junior scientist interested in pursuing a career in chemical biology?”

The long-awaited crystal structure of the Varkud satellite (VS) ribozyme dimer provides atomic-level insights into how the VS ribozyme folds and catalyzes RNA circularization during rolling circle replication, as well as revealing convergent evolution used by RNAs to catalyze an S_N2 reaction.

Multiple mitochondrial components generate reactive oxygen species (ROS), but separating the consequences of each ROS-generating source from overall mitochondrial health is challenging. A new class of small-molecule inhibitors that selectively block ROS generation from one of the most active sources may provide a new approach toward achieving that goal.

Meropenem/piperacillin/tazobactam is a triple β-lactam combination that kills MRSA in vitro and in a mouse model through a novel synergistic mechanism of action. Similar activity for other carbapenem/β-lactam combinations suggests that MRSA infections might be treatable with combinations of established β-lactams currently classified as ineffective against MRSA.

High-throughput chemical screening identified several groups of compounds that selectively block superoxide production from the outer Q-binding site of mitochondrial complex III and protect against ROS-induced oxidative stress in pancreatic β cells.

The identification and characterization of two cytochromes P450 from cabbage establish the biochemical basis for synthesizing brassinin-based phytoalexins, using two different routes of S-heterocyclization to construct these important vegetable compounds.

Crystal structures of the full-length VS ribozyme show a domain-swapped dimer that reveals potential mechanisms for cis and trans processing, and suggest convergent evolution in the active site motifs across multiple ribozymes.

Structural and biochemical investigations of a xylosyltransferase in complex with a domain from its substrate Notch inform on the catalytic mechanism and the conformational rearrangements needed for substrate binding, while genetic analysis poses new questions in cancer biology.

Triple combinations of carbapenem, penicillin and β-lactamase inhibitor antibiotic classes are synergistic against MRSA through a mechanism involving allostery-based synergy and collateral sensitivity and can thus be applied at doses that lead to less resistance.

The serine protease HTRA1 utilizes a "disintegration" mechanism involving its flexible PDZ domains to first loosen tau amyloid fibrils and subsequently disintegrating the fibrillar core structure for efficient proteolytic degradation.

Crystal structure of the Type ISP restriction enzyme−DNA complex and single-molecule studies reveal that DNA cleavage occurs through remodeling of ATPase-DNA interactions resulting in translocation of the enzyme without loop formation.

Gain of function mutations in isocitrate dehydrogenase 1 (IDH1) have been detected in cases of acute myeloid leukemia (AML). The application of an allosteric IDH1 inhibitor in AML cells promotes blast differentiation and restores DNA cytosine methylation patterns.