Volume 15 Issue 6, June 2019

Endocytosis mediates the internalization of proteins and lipids at the plasma membrane and plays essential roles in plant growth and development. A new small molecule enables manipulation of plant endocytosis in an acute and transient manner.

The NLRP3 inflammasome contributes to pathogenic inflammation in a broad range of diseases, making it a highly relevant drug target. Two studies published in this issue found an inhibitor of NLRP3 inflammasome activation to directly bind NLRP3 within its central NACHT domain, interfering with ATP hydrolysis and structural changes critical for NLRP3 oligomerization and subsequent inflammasome formation.

MCC950, a small-molecule inhibitor of the NLRP3 inflammasome, interacts directly with NLRP3 at the Walker B motif that hydrolyzes ATP, as defined by a protease-susceptibility assay, mutational analysis, and surface plasmon resonance analysis.

MCC950, a small-molecule inhibitor of the NLRP3 inflammasome, inactivates NLRP3, including hyperactive disease-linked mutations, by closing the ‘open’ conformation, thereby preventing conformational changes required for NLRP3 activation.

High-throughput screening identifies compounds that target insulin-degrading enzyme (IDE) and X-ray co-crystallography reveals how these compounds block insulin degradation by IDE but support its proteolysis of other substrates, including glucagon.

Structural and biochemical analyses identify Nudt12 as a novel mRNA deNADing enzyme in mammalian cells, which has a different substrate preference compared to the deNADing enzyme DXO.

Bioactive sesquiterpenes accumulating in petunia stigmas are synthesized in the floral tube and then transported to the pistil via natural fumigation within the internal airspace of the developing flower.

Optogenetically controlling the assembly of enzyme clusters enhances product formation and specificity during deoxyviolacein biosynthesis by decreasing concentrations of intermediate metabolites and reducing flux through competing pathways.

A potent inhibitor for hepatocyte growth factor was identified that utilizes an allosteric mode of inhibition revealed by atomic force microscopy imaging. The inhibitor could be used for positron emission tomography imaging of mouse tumors.

Structural analysis of uracil DNA glycosylases in complex with DNA reveals that conserved H109 acts as a nucleophile to attack the oxocarbenium ion and makes a covalent bond to the abasic site after uracil excision to form a stable intermediate.

Structural analysis of uracil DNA glycosylase reveals that its high affinity with DNA substrates derives from a stable intermediate that is formed by conservative H109 in a protruding loop covalently binding to the abasic site after uracil is excised.

A photoswitchable analog of spingosine-1-phosphate (S1P) that allows for modulation of the action of this bioactive lipid exhibits prolonged metabolic stability compared to S1P, activates S1P receptors in cells and mediates nociception in mice.

Reconstitution of β-Kdo-based capsular polysaccharide biosynthesis and crystallographic analysis of KpsC, a glycosyltransferase with two active sites for β-Kdo-glycolipid primer extension, reveal a new glycosyltransferase structural family.

Affinity-based target isolation and X-ray crystallography enabled identification of the non-protonophore ES9-17 as an inhibitor of the clathrin heavy chain in plants, enabling disruption of endocytosis.