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Orthogonal cholesterol sensors that are useful for imaging cholesterol in the plasma membrane leaflets reveal an asymmetry in which a high outer leaflet concentration is important for signaling processes and is potentially actively maintained.
The synergistic effect of the GPCR β2AR on signaling through another GPCR, PTHR, is explained by the release of Gβγ from the heterotrimeric Gαiβγ protein, activating adenylate cyclase AC2 and subsequent prolonged cAMP signaling in internal compartments
The development of small-molecule fluorescent probes through addition of a lipidated cysteine residue next to a caged fluorophore enables detection of endogenous cysteine depalmitoylation by acyl–protein thioesterases in vitro and in live cells.
The ‘CoINPocket’ approach identifies pharmacological similarities between G protein–coupled receptors. On the basis of predicted pharmacological similarity to a few phylogenetically unrelated receptors, the approach identified surrogate ligands for the orphan receptor GPR37L1.
A high-throughput screen identifies inhibitors of the M. tuberculosis dormancy regulation system, DosRST, including compounds that inhibit autophosphorylation of the DosS and DosT sensor kinases and those that inhibit the catalytic heme of these kinases.
Structural and functional characterization of an aromatic prenyltransferase reveals a unique spacious hydrophobic pocket with conformational fluctuation and multiple acceptor binding sites that endow it with uncommon enzymatic promiscuity.
Dimeric bis-benzimidazole compounds that bind selectively to toxic expanded r(CUG) RNA repeat sequences were identified and used as a scaffold for covalent modification, site-specific cleavage and on-target assembly of imaging reagents at expanded r(CUG) sequences in cells.
Synthetic biology enables re-engineering of cellular functions by introduction of modular, orthogonal signaling pathways, as illustrated by the reprogramming of human T cells to produce IL-2 in response to vascular endothelial growth factor (VEGF).
Single-molecule force spectroscopy and thermodynamics studies reveal six conformational states in the formation of a guanine aptamer, with a ‘kissing loop’ playing a key role in the conformational switching.
A mycobacterial phosphodiesterase, CdnP, hydrolyzes bacteria-derived 3′,5′-c-di-AMP as well as host-generated 2′,3′-cGAMP, which activates the host cytosolic surveillance pathway, to dampen host responses.
Metabolic labeling of the Drosophila proteome using a chemical ligation approach identifies proteins modified by O-GlcNAc transferase (OGT) including Polycomb proteins at homeotic gene loci and at unexpected sites, implicating OGT in gene-expression regulation.
Mass-spectrometry-based proteomics led to the identification of NoBody, a microprotein translated from LINC01420 RNA, which interacts with enhancer of decapping 4 (EDC4) and negatively regulates 5′-to-3′ mRNA decay.
Saturation mutagenesis, molecular modeling and biochemical analysis revealed that active site interactions involving Thr1372 of TET2 are responsible for controlling its proficiency for stepwise oxidation of 5-methylcytosine residues within DNA.
The use of fluorescence-polarized microscopy, combined with competitive binding with matched fluorescence companion imaging probes, enable target engagement measurements of covalent and reversible small molecule inhibitors in a single cell.
The iron protein components of bacterial nitrogenases are capable of reducing carbon dioxide (CO2) to carbon monoxide (CO) in the absence of their catalytic partners, mimicking the activity of CO dehydrogenase.
Super-binding peptides based on sequences of glycine receptors that interact with the neuronal scaffold protein gephyrin are useful for isolating and localizing native gephyrin and for modulation of glycinergic synaptic transmission.
Hydrogen–deuterium (H/D) exchange combined with NMR spectroscopy analysis of nucleosomal arrays identified an acidic patch on ubiquitin that mediates chromatin decompaction and further supports that ubiquitin–ubiquitin interactions are needed for chromatin solubilization.
Single-molecule high-resolution optical trapping techniques elucidate the molecular mechanisms underlying the unwinding of RNA duplexes by the helicase Mtr4p, including how it restricts directional translocation to duplex regions.
A sulfonamide series lacking the prototypical side chain behave as full antagonists or inverse agonists of estrogen receptor (ERα) signaling in a graded fashion dependent on coactivator recruitment and helix-11 positioning.
Computational design enables the generation of a chimeric construct of the RAS exchange factor SOS that is specifically activated by a small molecule. The expression of this construct in different cell types reveals distinct phosphorylation kinetics.
