Therapeutic targeting of the oncogenic NRAS protein, which is constitutively activated in human cancers, with small molecules is a promising yet challenging anticancer strategy. Therefore, targeting the NRAS mRNA poses a feasible alternative that will likely yield new biological consequences due to the new mechanism of regulation at the post-transcriptional level. We report herein the first examples of a reversely regulating NRAS mRNA-degrading ribonuclease targeting chimeric small molecules (NRAS-RIBOTAC), which were assembled by conjugating a reported 4-aminoquinazoline G4-NRAS binder with a biphenyl RNase L binder. Among the obtained NRAS-RIBOTACs, 5 impacted G4-containing NRAS mRNA expression while it did not significantly impact the expression of NRAS protein in MD-MB-231 cells, which could be explained by the fact that the G4-containing NRAS transcript only accounts for a trace amount in comparison with the dominant G4-lacking NRAS mRNA. Furthermore, we report here for the first time the phenotypic evaluation of RIBOTACs in the unbiased phenotypic profiling method, cell painting assay. In comparison with the monovalent ribonuclease recruiter and G4-NRAS mRNA binder, selected RIBOTACs showed significant activities in inducing cellular morphological changes and demonstrated a new biological performance that is reflected by the diverse cellular morphological changes in cancer cells.

DUBs regulate key cellular processes, but selective tools are scarce. Here, the authors developed PROTACs for the DUB USP7, comparing degraders with inhibitors. The study provides a valuable toolbox f...

Evolutionarily related ‘proto-point’ centromeres providing resolution to the evolutionary origins of point centromeres are identified in yeast, and comparison shows they evolved in an ancestor with re...

Als Wissenschaftlerin steht Lise Meitner auf einer Stufe mit Einstein, Heisenberg und Otto Hahn. Sie war 48-mal für den Nobelpreis nominiert. Ihre Geschichte erzählt vom Kampf gegen Diskriminierung, d...

The histone H3 variant CENP-A is considered an epigenetic landmark of centromeres. Its deposition reflects cell-cycle-regulated assembly of M18BP1, HJURP, and PLK1 on a divalent MIS18α/β scaffold. The...

In targeted protein degradation, a degrader molecule brings a neosubstrate protein proximal to a hijacked E3 ligase for its ubiquitination. Here, pseudo-natural products derived from (−)-myrtanol—iDeg...

Cells depend on early protein modifications for proper function. Here, the authors show that when Src-family signaling kinases lack their typical myristoylation, an alternative acetylated start is det...

The combination of bicyclic monoterpene- and pyrrolidine-alkaloid fragments yields novel pseudo-natural products. Biological characterization revealed that these iDegs are inhibitors and degraders of...

The dysregulation of the inositol-requiring enzyme 1 alpha (IRE1α) has been associated with multiple human diseases, so IRE1α-targeting small molecules present great therapeutic potential. Here, the authors report a series of substituted indoles as IRE1α inhibitors of good potency and selectivity, and show that the inhibitor IA107 allosterically inhibits IRE1α RNase activity via binding to the IRE1α kinase domain but without inhibiting the IRE1α dimerization.

Myeloperoxidase, a highly expressed neutrophil protein, disassembles nucleosomes, facilitating neutrophil extracellular trap (NET) formation, and binds stably to NETs extracellularly.

The kinetochore fibrous corona docks on CENP-E and a second elusive receptor identified as the checkpoint protein BUB1.

Structural insights into ultrafast Ca2+ transport by plasma membrane Ca2+-ATPases are provided, highlighting an essential role for PtdIns(4,5)P2 dynamics.

Activation of PLK1, a master mitotic kinase, requires phosphorylation of its activation segment on Thr210, within a basic consensus sequence for Aurora kinases. Aurora B-dependent phosphorylation of T...

Condensin I and II promote the drastic spatial rearrangement of the human genome upon mitotic entry. While condensin II is known to initiate this proc…

Arp2/3 complex is a central actin filament generator driving numerous motile processes in cells. It was originally isolated from Acanthamoeba approx. …

The spindle assembly checkpoint protects cells from chromosome missegregation. Here, the authors use sophisticated biochemical reconstitutions to address how kinetochores, the microtubule-binding stru...

Kazi et al. report the crystal structure of the mitochondrial deubiquitinase USP, a clinical stage Parkinson’s disease drug target, in complex with a specific inhibitor. The authors delineate a framework for specific deubiquitinase inhibition.

The indole moiety is a privileged fragment that frequently populates existing bioactive compound collections. We describe the development of an indole-dearomatization sequence and its application for....

imageimageFormation of Rho GTPase activity patterns on the plasma membrane is key to numerous morphogenic processes in eukaryotic cells. This study employs a reconstitution approach to reveal the bioc...

FAcilitates Chromatin Transcription (FACT), which stabilizes chromatin during transcription and replication, is mysteriously enriched at mitotic kinetochor