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Enzymes are increasingly important in industrial-scale chemical transformations, but identifying or engineering an enzyme that displays the desired function is not always possible. Selecting monobodies (yellow ovals) that sterically block the extended binding site of a galactosidase (gray oblong shapes) provides an alternative strategy to control the specificity of oligosaccharide products (grey and pink circles) without altering the galactosidase directly. Cover art by Erin Dewalt based on an image from Yoko Koide. Brief Communication, p762
The recent emergence of signaling roles for transition metals presages a broader contribution of these elements beyond their traditional functions as metabolic cofactors. New chemical approaches to identify the sources, targets and physiologies of transition-metal signaling can help expand understanding of the periodic table in a biological context.
Chemical compounds designed to enhance understanding of host-pathogen interaction together with next-generation 'smart drugs' will rationally drive the discovery of promising new host-directed targets against pathogens including Mycobacterium tuberculosis, the causative agent of tuberculosis.
Iron availability plays a decisive role in host-pathogen interaction, and limitation of iron availability to microbes has been characterized as an effective host defense strategy. The identification of the iron-scavenging property of the neutrophil protein calprotectin adds an important new piece to this concept of nutritional immunity.
The essential metabolic cofactor coenzyme A was believed to be produced by biosynthesis from pantothenate in all eukaryotic cells. Rescue experiments in systems depleted of CoA have shown that a phosphorylated CoA biosynthetic intermediate can pass through eukaryotic membranes to serve as an alternative source.
A new small-molecule inhibitor of the autophagy-initiating kinase ULK1 serves to block a critical survival mechanism activated upon inhibition of mTORC1, potentially enhancing treatment efficacy for mTOR inhibitors currently in clinical trials for cancer treatment.
The four-helix bundle is a simple structural motif, widespread in nature, that is involved in numerous and fundamental processes. This portfolio is now expanded by the report of a four-helix bundle protein able to store copper for particulate methane monooxygenase, an enzyme that catalyzes methane oxidation.
Enzyme engineering can yield changes in substrate specificity, but limited options exist when mutations are not causing the desired outcome. Selection of monobodies that bind near, but not at, a galactosidase active site now offers another avenue for altering product profiles.
Calprotectin sequesters manganese and zinc from bacteria, preventing their growth. Spectroscopic and biological data show it also chelates iron with sub-picomolar affinity using a hexahistidine motif, establishing a new mechanism for its antibacterial activity.
Structural and biophysical evidence demonstrating that glutaredoxin-3 passes [2Fe-2S] clusters to anamorsin during a protein-protein interaction mediated by their N-terminal domains define the early steps of iron-sulfur cluster protein maturation.
Drug metabolism in humans is typically discussed in terms of P450 reactions, but growing evidence indicates aldehyde oxidase plays a central role as well. The first crystal structures of the human enzyme reveal a flexible tunnel to the active site and a new inhibitory site.
Cellular use of coenzyme A from external sources requires the hydrolysis of extracellular coenzyme A into 4′-phosphopanthetheine, which can cross the membrane. CoA synthase subsequently converts intracellular 4′-phosphopanthetheine into coenzyme A.
Linking a peptide with a small-molecule ligand for the serum protein transthyretin ensures half-life extension without diminishing potency through protection against proteases and decreasing glomerular filtration.
An RNAi strategy and a new fluorescent ceramide help identify the transmembrane protein LAPTM4B as facilitating export of ceramide from late endosomes. This activity sensitizes tumor cells to drugs that induce ceramide-driven apoptosis.
A quantitative chemical proteomics approach identified the DNA damage response mediator 53BP1 as a direct reader of the phosphorylated histone variant γH2AX in cells.