In this issue of Structure, Shang and Kojetin (2021) present insights into the binding mechanism of artificial agonists to the PPARγ nuclear receptor. These data support a two-step model with induced fit and conformational selection aspects. This mechanism may exist in related receptors, providing new opportunities for drug development.

In this issue of Structure, Gadjos et al. (2021b) determine the structure of a bacterial lectin in complex with L-fucose by neutron diffraction of both perdeuterated protein and carbohydrate ligand. The structure provides insight into lectin-ligand interactions, opening avenues for drug design targeting bacterial lectins for intervention in infectious disease.

COPII vesicle biogenesis at the endoplasmic reticulum requires activation of the Sar1 GTPase, which recruits the COP II coat protein complex to drive membrane budding. In this issue of Structure, Joiner and Fromme (2021) investigate the enigmatic structural basis for Sar1 activation by the Sec12 guanine nucleotide exchange factor.

The bacterial Sec translocase transports unfolded proteins across membranes. In this issue of Structure, Krishnamurthy et al. (2021) report a nexus of conformational dynamics in the translocase motor protein, SecA. Their findings shed light on the Sec activation mechanism and suggest a general role for multi-level dynamics in protein functions.

In this issue of Structure, Aiyer et al. (2021) report NMR structures of BET:MLV IN complexes, highlighting a role for the disordered tail domain of MLV IN in viral integration. These studies expand the understanding of molecular recognition polymorphism in BET complexes and offer insight into cancer and antiviral therapeutics.

Astrocyte-secreted Hevin induces synapse formation by bridging the trans-synaptic organizers, neuroligins and neurexins. In this issue of Structure, Fan et al. (2021) elucidate the structural basis of Hevin’s interaction with these molecules and reveal the competitive interplay between Hevin, SPARC, and MDGAs.

In Cell Chemical Biology, Naineni et al. (2021) report the structure of a synthetic analog of the translation inhibitor pateamine A bound to initiation factor eIF4A and RNA. The drug stacks with RNA bases in the same pocket where unrelated rocaglate compounds bind, highlighting a druggable site for DEAD-box proteins.

The functions of Ras members are largely governed by the structural dynamics of the nucleotide-binding switch regions. In this issue of Structure, Lin et al. (2021) take a close look at the dynamic equilibrium of RhoA, the founding member of the Rho family of Ras GTPases.

Dynamic nuclear positioning requires the formation of robust connections between the cytoskeleton and components of the LINC complex, a protein assembly that spans the nuclear envelope. A new study by Lim et al. (2021) reveals the mechanism of association between the LINC complex proteins Nesprin-1/2 Giant and the cytoplasmic formin FHOD1.

Most type II restriction modification systems employ rigorous mechanisms to interrogate methylation in both DNA strands to distinguish between host and invader DNA. Type IIL enzymes like DrdV are an exception to this rule. In this issue of Structure, Shen et al. (2021) address how such enzymes make the distinction successfully.

Fusion products with the ETS family of transcription factors play critical roles in the etiology of several cancers. In this issue of Structure, Hou et al. (2020) provide insight into allosteric mechanisms by which mithramycin and its analogs perturb protein-DNA interactions in higher-order complexes at a DNA enhancer site.