In this issue, Nature Chemical Biology examines the past, present and future of chemical biology. Cover art by Erin Dewalt based on an image from ©iStockphoto.com and scientific icons by Katie Vicari. Editorial p845; Feature pp847-854; Grand challenge commentaries pp857-879; Primer (bound insert).

Protein biocatalysts are powerful tools for small-molecule synthesis, but identifying enzymes that can catalyze new reactions is challenging. Höhne et al. report a new strategy to find existing (R)-selective transaminases in which rationally developed structural motifs are used to search sequence space for suitable candidates, yielding 17 active enzymes with 100% success. The cover demonstrates that with the right sequence information, new catalysts are ripe for the picking. Cover art by Erin Dewalt, based on art from Matthias Höhne and Sebastian Schätzle and an original image from ©iStockphoto.com/ Alexandr Makarov. Article p807; News & Views p793

Structural and functional diversity are observed throughout biology. This polarizing microscope image of chiral liquid crystal nuclei emerging from an isotropic melt provides a stunning display of how spatial and structural heterogeneity can emerge from seemingly homogenous conditions. In the dark background, there is no order. As nuclei form, the details of the molecular arrangements change depending on phase and from one nucleus to another, with parallel alignments of the molecules creating a twist that can either be suppressed or developed into a periodic stripe pattern. Cover art by Erin Dewalt, based on an original image provided by Bohdan Senyuk and Oleg D. Lavrentovich (Liquid Crystal Institute, Kent State University).

Zinc ions are important signaling agents in oocyte maturation. Total zinc content increases in maturing oocytes, and zinc insufficiency causes meiotic arrest midway through reductive division with the spindle apparatus stalled at telophase I. The cover pictures a cell that is arrested in telophase I and stained for α-tubulin (magenta), F-actin (green) and DNA (yellow). Cover art by Erin Boyle, based on artwork provided by Alison Kim. Article p674

Discovery of a stapled peptide inhibitor of Mcl-1. Stewart et al. screened a library of stapled peptides based on the BH3 domains of BCL-2 family proteins (library depicted on left) and identified a selective inhibitor of MCL-1 (structure of the inhibitor in complex with Mcl-1 shown on the right), one of the anti-apoptotic family members that plays a key role in the survival of cancer cells. The peptide inhibitor, derived from the BH3 domain of MCL-1 itself, sensitizes cancer cells to caspase-dependent apoptosis, providing a novel tool to study and modulate this potential drug target. Cover art by Erin Boyle, based on artwork provided by Eric D. Smith. Article p595; News & Views p566

Lipids are critical chemical components of cells, forming the basis of biological membranes that organize and compartmentalize cellular functions. Lipids are also important mediators of biochemical signaling events, both as components of membranes and as second messengers. This issue contains a collection of articles that discuss our current understanding of the functions of lipids and the methods used to study them at the individual level and within the larger biological systems in which they function. Cover art by Erin Dewalt, based on an image from Raghuveer Parthasarathy of the topology of a supported lipid bilayer containing red and green fluorescently labeled glycoproteins, acquired using fluorescence interference contrast microscopy.

Nature Chemical Biology celebrates five years of publishing the very best of chemical biology research, opinion and analysis. Cover art by Erin Dewalt.

To discover the origin of high affinity protein-ligand interactions, it is important to determine the contribution of conformational entropy. In a new approach, Marlow et al. have quantified the change in conformational entropy upon binding of peptides to the model protein calmodulin from changes in order parameters of methyl groups as determined by deuterium NMR relaxation spectroscopy. This required the development of an empirical calibration of the relationship between protein motion and conformational entropy. In addition, motion at the interacting protein surfaces is surprisingly variable and often noncomplementary. Cover art by Erin Dewalt, based on original artwork from Erica Wand. Article p352; News & Views p312

Robust and straightforward methods for producing mammalian N-linked glycoproteins are needed to advance glycoprotein research and the development of protein-based therapies. Schwarz et al. have engineered a new glycosylation pathway, combining elements from C. jejuni and E. coli, to create a key GlcNAc-Asn linkage in expressed proteins that can be further remodeled using known strategies. The cover shows the last step of this process, in which the trimmed, GlcNAc-modified sequence is attached to a ready-made glycan to yield the desired mammalian glycoform. Cover art by Erin Dewalt, based on an original image from Alessandro Palumbo, Flavio Schwarz and Carlo Zambon. Brief Communication p264

Chemical probes provide important tools for dynamically interrogating biological systems and for investigating potential drug targets. In this issue we feature a collection of Commentaries and Review Articles that highlight recent advances and future directions in the field. On the cover, we highlight three research papers in this issue that describe advances in chemical probe research: using new biochemical assays, Bradner et al. discover unexpected selectivity within current HDAC inhibitors and develop a true pan-HDAC inhibitor (p238); Kokel et al. describe a method for identifying neuroactive molecules and predicting their mode of action through behavioral zebrafish assays (p231); and Bracha et al. use a combination of RNAi, metabolomics and chemical probes to uncover metabolic enzymes that regulate myoblast differentiation (p202). Cover image by Katie Vicari, based on artwork provided by Sigrid Hart (phylogenetic trees), Randall Peterson (zebrafish images) and Felice Frankel (cell images).

Phosphoinositide-3-OH kinase (PI(3)K) inhibitors with a wide range of selectivities have entered clinical development. Berndt et al. report the structure of the catalytic core of the PI(3)Kδ isoform alone and in complex with isoform- and panselective PI(3)K inhibitors, providing new insights into mechanisms of selectivity and potency. Shown is a superposition of the IC87114- and the SW14-bound structures of p110δ. In both structures, Met752 moves to open up the hydrophobic specificity pocket. SW14 has an additional moiety that interacts with the affinity pocket. Cover image by Katie Vicari, based on artwork provided by Alex Berndt. Article p117; News & Views p82

Transitions between the aqueous phase and a lipophilic environment are key steps in the fate of many proteins. Gerlach et al. probed the binding kinetics of the myristoylated HIV-1 Nef protein to liposomes. Shown is an artist's view of lipid drops in a cytosolic environment that reflects a highly dynamic interplay where defined membrane composition, liposomal curvature and sequence motifs modulate and drive Nef-lipid interactions. Cover art by Erin Boyle, based on artwork provided by Eberhard Ross. Article p46