Research articles

Although JAK2 inhibitors were proposed to be beneficial in chronic myeloid leukemia, myeloid transformation and STAT5 activation in BCR-ABL–positive leukemias are JAK2 independent. Mechanistic investigations reveal that certain JAK2 inhibitors act via off-target inhibition of BCR-ABL.

The combination of a caged morpholino and a photoactivated fluorophore, allowing isolation of targeted cells by FACS, and subsequent transcriptional profiling reveals new and temporally distinct targets for Ntla during notochord development in zebrafish.

Untargeted metabolomics reveals a dysregulation of sphingolipid production during neuropathic pain exemplified by N,N-dimethylsphingosine, whose upregulation is involved in the generation of pain.

Semisynthetic constructs of protein kinase CK2 incorporating nonhydrolyzable post-translational modifications now demonstrate the interplay between phosphorylation and glycosylation in regulating CK2 stability, controlling substrate specificity and modifying interactions with regulatory proteins.

Glycosylation is a well-known post-translational modification, but identifying specific roles for the attached glycans is often challenging. The identification and investigation of a new O-GlcNAc site on the transcription factor CREB provides insights into how glycosylation works together with phosphorylation to coordinate neural function.

NMR and structural analyses of DHFR complexes with inhibitors of differing affinities define a model for ligand dissociation involving conformational switching and a new excited state that mediates the dissociation.

Osmolytes act as chemical chaperones capable of directly assisting the folding of destabilizing mutations in proteins in vivo, with different osmolytes having distinct targets and thereby increasing the level of genetic variability.

20(S)-hydroxycholesterol binds to Smo at a site distinct from cyclopamine and activates signaling via an allosteric mechanism. A new alkyne oxysterol analog selectively captures Smo from membrane extracts and provides a new method for detecting protein-sterol interactions.

DNA repair proteins require efficient pathways to search for DNA damage lesions within a large genome. Kinetic trapping experiments define the rates of human uracil DNA glycosylase hopping and sliding along damaged DNA substrates and highlight the role of the phosphodiester backbone in DNA sliding.

Mucopolysaccharidoses are caused by a deficiency in GAG processing and can often be treated if the dysfunctional enzyme can be identified. A chemical derivatization strategy in combination with biochemical logic now yields a series of biomarkers that can be used to distinguish these disorders.