Volume 13 Issue 12, December 2017

The 'off-targets' of a drug are often poorly characterized yet could be harnessed in the treatment of complex diseases. A recent study used a small-molecule screening in non-small-cell lung cancer to repurpose an FDA-approved ALK/IGF1R inhibitor and uncover its mechanism of action.

Phage-assisted evolution can rapidly improve the efficiency and substrate specificity of orthogonal aminoacyl-tRNA synthetases. Furthermore, the crystal structure of the pyrrolysyl-tRNA synthetase N-terminal domain reveals the basis for these improvements and provides a structural rationale for orthogonality.

An inhibitor of the deubiquitinase (DUB) USP10 regulates the degradation of oncogenic FLT3, thus defining USP10 as a DUB for FLT3 and providing a therapeutic approach for human acute myeloid leukemia in which FLT3 activation is dysregulated.

Kinetic analysis and EPR spectroscopy measurements on a bacterial heme-nitric oxide/oxygen-binding (H-NOX) protein reveal that nitric oxide (NO) binds on the distal side of the heme cofactor under both limiting and excess NO conditions.

A systems chemical biology approach to characterize beneficial off-target effects revealed a polypharmacology mechanism for the multikinase inhibitor ceritinib and a repurposing opportunity through rational design of a synergistic drug combination.

A linear gating mechanism links kinetically and structurally distinct closed and open states of NMDA receptors. During allosteric inhibition, agonist binding incudes uncoupling of structural changes from gating motions in the first transmembrane region.

The natural product stendomycin is a first-in-class inhibitor of the TIM23 mitochondrial translocon in yeast and mammalian cells that helped reveal that the TIM23 complex does not regulate transport of the autophagy regulator PINK1.

Microtubule sliding driven by kinesin-14 HSET is regulated by a feedback mechanism. When microtubules start sliding apart, HSET molecules are retained in the shortening overlap, which leads to an HSET-density-dependent decrease in sliding velocity.

The use of phage-assisted continuous evolution (PACE) with both positive and negative selection enables the rapid development of orthogonal aminoacyl-tRNA synthetases with high activity and selectivity for noncanonical amino acids.

The N-terminal domain structure of pyrrolysyl-tRNA synthetase (PylRS) reveals details of its tRNA specificity and facilitates the improvement of its selectivity for non-canonical amino acids by phage-assisted non-continuous evolution (PANCE).

N-Acetylglucosamine derivatives equipped with electrophilic groups and handles for subsequent chemical tagging are useful probes of substrate recognition by O-GlcNAc transferases and enable the capture of transient protein substrates of these enzymes.

A positive-selection CRISPR screen with the pro-oxidant paraquat (PQ) uncovers three genes mediating PQ-induced cell death: POR is the source of PQ-mediated reactive oxygen species (ROS) generation, and ATP7A and SLC45A4 promote oxidant-dependent cell death.

The development of a computational protein design method, meta-multistate design, enables the design and validation of protein variants termed DANCERs that spontaneously exchange between predicted conformational states on the millisecond timescale.