Articles in 2014

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 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.

Peptide macrocycles are attracting increasing attention as tools for research and as potential therapeutics. The highly efficient butelase 1—homologous to proteases but specific for ligations—offers a new method for peptide cyclization.

Finding evolutionary links between protein superfamilies has proven challenging. Advanced bioinformatics tools now identify relationships across two superfolds as well as a hybrid family whose structure displays characteristics of both.

ABPP combined with quantitative MS enabled identification of specific on- and off-targets of covalent kinase inhibitors. Modifications to inhibitors that alter specificity beyond a defined window can promote kinase-independent toxicity.

(+)-7-iso-jasmonoyl-L-isoleucine (JA-Ile) is a plant hormone involved in plant development and stress response that signals through a COI1–JAZ co-receptor complex. Structure-guided design led to the identification of a coronatine derivative that antagonizes the COI1-JAZ interaction and blocks jasmonate signaling in plants.

C-terminal extended ubiquitin species, which have been associated with neurodegenerative disorders, were thought to inhibit proteasomes resulting in reduced protein clearance. Biochemical studies now provide evidence that these ubiquitin variants primarily block the activity of the deubiqutinating enzymes.

The development of a new screening method called EnPlex allows rapid profiling of small molecules against an extensive selection of the serine hydrolase enzyme family, resulting in the identification of both off-targets and potential lead compounds.

Inclusions containing TDP43 are linked to pathologies in several neurodegenerative diseases such as ALS and FTD. Pathogenic TDP43 mutations are now found to shorten the protein's half-life in individual neurons. Stimulating autophagy with inhibitors improves TDP43 clearance and localization.

Some toxic natural products are made in deactivated forms to avoid damage to the host. Metagenomic mining of sponge symbionts and biochemical characterization now define a new inactivating mechanism in which calyculin is made as a pyrophosphate by symbiotic bacteria and cleaved to the active monophosphate by the sponge.

Polybrominated aromatic natural products are pervasive in the marine food web. Genetic and biochemical data now establish their biosynthetic origins in marine bacteria, revealing a physiological brominase that uses an unusual decarboxylative mechanism.

The addition of a Notch signaling inhibitor to both mouse and human keratinocytes bypasses the use of oncogenes and p53 to increase transcription factor mediated–pluripotent stem cell reprogramming through blocking p21 expression.