Using a modified version of the in silico screening tool, DOCK, compounds that covalently modify catalytic and noncatalytic protein nucleophiles find compounds that modulate the activities of bacterial β-lactamase (AmpC) and the kinases RSK2, MSK1 and JAK3, including a first-in-class inhibitor for JAK3. Shown is a new JAK3 reversible covalent inhibitor docked to JAK3 (white) sampled at different orientations around the covalent bond to the active site cysteine (rainbow). Cover art by Erin Dewalt, based on an image from Brian Shoichet. Article, p1066

Proteostasis regulates protein synthesis, folding and degradation programs to ensure that the integrity of the proteome remains intact. A collection of Commentary, Perspective and Review articles in this issue describe new advances in understanding the mechanisms of proteostasis and how chemical biological approaches can be used to restore protein homeostasis. The cover image depicts a conveyor belt containing a mixture of folded and misfolded proteins, which are surveyed by the protein quality control network. Unfolded proteins are directed through the black window, where they undergo ubiquitin modification (shown by the Ub label) and degradation by the proteasome (depicted here by the shredder). Cover art by Erin Dewalt.

Jasmonate derivatives regulate numerous defense and developmental pathways in plants. A chemical screen in Arabidopsis thaliana identified jarin-1 as an inhibitor of jasmonate biosynthesis and a potential chemical probe of jasmonate signaling. The cover features an A. thaliana reporter system used to identify jarin-1, in which successfully transformed individuals (green seedlings) were identified by virtue of their resistance to kanamycin, which otherwise kills them (yellow seedlings). Cover art by Erin Dewalt, based on imagery from Erich Kombrink. Article p830

Macrocycles are thought to provide new entry points in drug discovery based on their distinct properties as compared to small molecules, but unknown design rules and limited synthetic methods for these diverse molecules have impeded progress in the field. Three papers now provide computational, informatic and biochemical updates to enable macrocycle development and target binding. Cover art by Erin Dewalt, based on imagery from Torsten Lorenz / Alamy. Articles, pp716, 723 and 732; News & Views, p696

The ability to reprogram different somatic cell types into induced pluripotent stem cells (iPSCs) has revolutionized the stem cell community and spurred the development of new strategies to improve the frequency. A new study reveals that small molecule–mediated inhibition of Notch signaling promotes the reprogramming of mouse and human keratinocytes into iPSCs. The cover features an iPSC colony produced from human keratinocytes stained with TRA-1-81 (red), NANOG (green) and DAPI (blue). Cover Art by Erin Dewalt, based on imagery from Justin Ichida and Kevin Eggan. Article p632

Light enables and controls life through processes such as photosynthesis, vision and circadian rhythms. Light also serves as a rich resource for scientific study, where it has been coopted as a reagent and tool. A collection of Perspective and Review articles in this issue describes biological responses to light and our increasing ability to use light to uncover new scientific information. Cover art by Erin Dewalt.

Protein design and engineering have typically focused on static structures to guide selection of mutations or other changes to be made, but dynamics have increasingly been viewed as a missing element in these approaches. Two manuscripts now provide computational and biophysical evidence that dynamics—as captured in this image as a film strip of protein conformations—has a major role in determining the success or failure of a protein design project. Cover art by Erin Dewalt, based on imagery from Sílvia Osuna with help from Gonzalo Jiménez-Osés and K. N. Houk. Brief Communication, p428; Article, p431

G-rich sequences within gammaherpesvirus genome maintenance protein (GMP) mRNA form G-quadruplexes (G4) that repress GMP translation. The cover features the Epstein-Barr virus and the regulation of ribosomal translation by small-molecule ligands or antisense oligonucleotides that either stabilize or destabilize G4 formation in the GMP mRNA. Cover art by Erin Dewalt, based on imagery from Judith Tellam and Pierre Murat. Article, p358

An untargeted metabolomics approach finds that ubiquinone-8 (Q8) accumulates in Escherichia coli with sustained hyperosmotic stress induced by NaCl (blue and purple molecules outside of the cell). Q8 (gray) functions to mechanically stabilize membranes (pink), contributing to acute and sustained stress tolerance, as shown by treating cells with various genetic mutations and an in vitro liposome assay. This new role for Q8 in stress tolerance does not involve its known roles in radical scavenging or as a respiratory electron carrier, and it depends on the octaprenyl chain (not the benzoquinone moiety). Cover art by Erin Dewalt, based on images and concept from Daniel C. Sévin. Article, p266; News & Views, p242

Engineered constructs offer new opportunities to understand and manipulate biological systems. This drawing illustrates the central concept of five manuscripts published in this issue that develop or use engineered designs. Cover art by Erin Dewalt.

QueE synthesizes a 7-deazapurine structure found in the tRNA base queuosine, the antibiotic toyocamycin and over 30 other natural products. Crystallographic and biochemical studies of QueE now provide molecular insights into the unusual features of this radical SAM enzyme. The cover features the active site of QueE with S-adenosylmethionine, a [4Fe-4S] cluster, a catalytically essential divalent metal cation and a substrate, all queued up for catalysis. Cover art by Erin Dewalt, based on imagery from Daniel Dowling and Catherine Drennan. Article, p106

High-throughput chemogenomic profiling (depicted in the shadow as a microarray) defined specific and potent small-molecule inhibitors of the phosphatidylinositol (PI) transfer activity of a yeast PI transfer protein, Sec14. Hovering over the membrane bilayer (bottom) are the transition states of Sec14 from its 'open' to 'closed' conformation. During this transition, the hydrophobic cavity is exposed simultaneously to lipid substrates and small-molecule inhibitors while Sec14 undergoes lipid exchange at the bilayer. Cover art by Erin Dewalt, based on images and concept from Ashutosh Tripathi. Article, p76