Articles in 2012

Auxin is perceived by a co-receptor complex that contains a TIR1 F-box protein and an Aux/IAA transcriptional repressor. The combinatorial diversity of auxin co-receptor complexes and their distinct spectra of affinities offer a means to tune plant cell sensitivity to a wide range of auxin concentrations.

A covalent inhibitor based on an electron-deficient olefin scaffold reversibly and selectively inhibits the p90 ribosomal protein S6 kinase RSK.

Diazepam-bound GABA_A receptor models used for virtual screening lead to discovery of new ligands that modulate GABA_A receptors expressed in Xenopus laevis oocytes via their benzodiazepine binding site.

Antisense RNA sequences are attractive 'parts' for use as regulatory devices in synthetic biology applications. Synthesis and testing of an RNA library specific to the translation initiation region now allows analysis and forward design of these sequences, leading to a family of mutually orthogonal regulators.

Chemically inducible protein dimerization serves as a useful tool to investigate biological systems and construct synthetic circuits. Optimization of a protein-protein interaction dependent on the plant hormone gibberellin yields a portable dimerization system that can be combined with rapamycin to assemble logic gates.

The protein phosphatase LYP is known to regulate signaling in the immune system, but the regulatory mechanisms controlling LYP itself are less clear. Exploration of spatiotemporal dynamics and application of a newly identified chemical inhibitor now define a role for the kinase CSK in dialing down LYP activity.

Macrocycles are well represented in natural product structures but have been challenging to access for inclusion in synthetic libraries. A new method uses ring expansion to convert fused small rings into macrolactones and macrolactams that occupy natural product–like chemical space.

Dipeptides transported by the yeast amino acid transceptor Gap1 act as persistent agonists by accumulating with the transceptor within endosomes and triggering rapid cytosolic acidification via Gap1's H⁺ cotransport function.

The unusual crosslinks between cysteine residues and the peptide backbone in the antibiotic peptide subtilosin A are formed by a new member of the radical SAM enzyme superfamily that contains two functionally linked [4Fe-4S] clusters.

TAME, an inhibitor of the ubiquitin ligase APC, promotes autoubiquitination and dissociation of Cdc20, an APC activator. In the presence of APC substrate, TAME decreases the catalytic activity of APC-Cdc20 complex and decouples substrate ubiquitination from proteasomal degradation.

A compound that inhibits hydrolysis of O-GlcNAc groups decreases the neurodegenerative capacity of tau, a protein that forms neurofibrillary tangles in Alzheimer's disease.

Studying specific cellular responses elicited by compartmented cAMP signals in real time has been difficult. A new method called SMICUS overcomes this challenge and reveals a resident pool of nuclear PKA that can convert cAMP signals to rapid responses.

DNA-templated macrocycles bind the ATP binding pocket of Src kinase, locking it into an inactive conformation. These small-molecule inhibitors compete with both ATP and substrate for binding and inhibit the T338I gatekeeper mutant version of Src.

An adamantyl urea derivative identified as a potent bactericidal compound against Mycobacterium species and multidrug-resistant M. tuberculosis targets a late step in biogenesis of very-long-chain cell wall–bound mycolic acids—by inhibiting the transport of the fatty acids across the bacterial plasma membrane.

Optimized negative-staining and cryo–positive staining EM reveals that human cholesteryl ester transfer protein penetrates into HDL and LDL from each distal end and potentially forms a continuous tunnel by connecting its internal series of isolated hydrophobic cavities together for cholesteryl ester transfer.

Halofuginone was recently shown to inhibit the differentiation of T helper 17 (T_H17) cells, which are associated with autoimmune diseases. The demonstration that halofuginone inhibits prolyl-tRNA synthetase activity explains the observed activation of the amino acid response pathway in T_H17 cells and identifies amino acid restriction pathways as potential drug targets in inflammatory disease.

Metals serve as unique structural and functional elements in biology, providing a wealth of reactivities not available in a wholly proteinogenic active site. The computational redesign and directed evolution of zinc enzymes to create a phosphotriesterase provides insights into how these elements can be utilized in the development of new functions.

Identifying DNA sequences that adopt alternative structures within the context of genomic DNA presents a major challenge. Pyridostatin, a G-quadruplex–specific chemical probe, was shown to induce DNA damage at specific genomic sites, including the proto-oncogene SRC, leading to cell cycle arrest in human cancer cells.

MLL fusion genes often encode leukemogenic proteins that depend on interaction with menin, a component of the MLL SET1-like histone methyltransferase complex. MI-2 and MI-3 are the first small molecules that can block menin–MLL fusion protein interaction and their oncogenic effects in cells.

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.