Research articles

Structural and biochemical studies of an acetyltransferase demonstrate that conformational changes differ depending on the ligand bound, indicating that binding cooperativity is more complex than expected.

Crystallographic analysis depicting the interaction of the kinase inhibitor SCH772984 with ERK1/2 reveals a unique binding pocket distinct from off-targets such as haspin and is associated with slow binding kinetics and prolonged inhibitory activity.

Single-molecule measurements show that HSV-1 DNA changes its stiffness by undergoing a solid-to-fluid transition within the capsid in the ionic environment of host cells and at a temperature that is optimal for viral infection.

HIV-1 binds host CD4⁺ T cells via its gp120 envelope glycoprotein that undergoes changes to allow ‘opening’ of the envelope trimer, exposure of gp41 and binding to the CCR5 co-receptor. Compound 18A inhibits HIV-1 infection by blocking some of these conformational changes.

Alloswitch-1 is a photoswitchable modulator for mGlu5, and it is the first photoswitchable allosteric GPCR modulator. It was generated by adding the azobenzene Ar-N=N-Ar scaffold into an existing positive allosteric modulator of the receptor.

The eukaryotic Elongator complex has been assigned multiple roles in transcription and tRNA modification. In archaea, the Elp3 component is a radical SAM enzyme that catalyzes the carboxymethylation of uridine in the wobble position of tRNA.

Metabolic engineering of yeast to incorporate plant and bacterial enzymes that construct and decorate morphine, along with spatial engineering to enable a spontaneous chemical reaction, provides strains capable of producing up to 130 mg/l of opioids.

Production of eukaryotic proteins in bacteria is limited by the specificity of the bacterial oligosaccharyltransferases that perform N-linked glycosylation. ‘GlycoSNAP’ simplifies the study of these enzymes, leading to mutants with relaxed specificity.

Jasmonate derivatives regulate numerous defense and developmental pathways in plants. A chemical screen in Arabidopsis thaliana identifies jarin-1 as an inhibitor of jasmonate biosynthesis and a potential chemical probe of jasmonate signaling.

A two-enzyme complex works as a cyclodehydratase to form TOMM natural products, but the roles of each protein have been unclear. Structural and biochemical analysis deconvolutes the roles of each protein and identifies a new ATP-binding motif.

A compound previously identified as a dopamine D2 receptor allosteric modulator was found to be a bitopic ligand that binds the orthosteric and allosteric sites to allow binding to one D2 protomer and allosteric modulation of the associated protomer.

SK potassium channels are activated by Ca²⁺-bound calmodulin (CaM) and regulated by phosphorylation. Electrophysiology and MD simulations show that a PIP₂-binding site formed at the interface of CaM and SK2, conferring PIP₂ sensitivity on the channels.

A small-molecule compound, GSK2194069, specifically inhibits the β-ketoacyl reductase (KR) activity of the human fatty acid synthase. A co-crystal structure of the KR domain with the inhibitor confirms this interaction.

Crystal structures of the ydaO riboswitch from two thermophilic bacteria reveal a square-shaped RNA architecture that is locked together by two c-di-AMP ligands that bind in pseudosymmetric binding pockets.

The bacterial ydaO riboswitch senses the second messenger c-di-AMP. Crystallographic and isothermal titration calorimetry analysis reveals that ydaO binds two molecules of c-di-AMP in binding pockets related by pseudo-two-fold symmetry.

A GPCR, the parathyroid hormone receptor, can elicit a sustained signal from internal membranes after internalization. The signal was found to be terminated by a feedback mechanism where PKA activates the proton pump v-ATPase, which acidifies endosomes.

A haploid screen in human cells identified the solute carrier protein family member, SLC35F2, as a determinant of the sensitivity of cells to the DNA damaging agent, YM155, by promoting YM155 import into cells.

The twister ribozyme is a recently discovered self-cleaving RNA that has wide distribution in bacteria and eukaryotes. A crystal structure of a twister ribozyme reveals a double-pseudoknot core that positions a conserved guanine near the scissile phosphate where it participates in general acid-base catalysis.

Protein-protein interfaces are stabilized by ‘hot spots’ of interactions; helices that drive some of these interactions have been used as inspiration for peptide inhibitors. A computational program called ‘LoopFinder’ now identifies protein loops that perform equivalent roles, revealing new opportunities to explore biology.

Macrocycles have the potential to act on currently undruggable targets, but their discovery thus far has been unsystematic. A physicochemical analysis of all nonredundant co-crystal structures now sets out guidelines for macrocycle development.