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Enzyme engineering can yield changes in substrate specificity, but limited options exist when mutations are not causing the desired outcome. Selection of monobodies that bind near, but not at, a galactosidase active site now offers another avenue for altering product profiles.
5-Formylcytosine (5fC), produced by TET-mediated oxidation of 5-methylcytosine, is considered an intermediate in active DNA demethylation. Labeling studies and LC/MS analysis across mouse developmental stages reveals that 5fC modifications are more persistent in the genome and may have other functional roles.
The use of a presumed chemical intermediate in the mechanism of enoyl thioester reductase enables the identification of the long-sought proton donor and the rational redesign of enzyme stereoselectivity.
Post-translational regulation of Cas9 activity may improve the specificity of genomic targeting. A modified version of Cas9 with an insertion of a small molecule–regulated intein allows temporal control of Cas9 activity and reduces off-target activity.
Establishing the existence of a Diels-Alderase—an enzyme that catalyzes a concerted [4 + 2] cycloaddition—is made easier by a crystal structure of SpnF, which, along with computational and biochemical analysis, should enable mechanistic investigations.
Modification of the CRISPR/Cas9 genome editing system by the addition of the light inducible proteins CRY2 and CIBI1 enables blue light–mediated transcription of endogenous genes in mammalian cells.
Membrane sorting of Ras and its isolated lipid anchor is based on membrane curvature, sensed by Ras itself. This helps to explain the previous inability to match in vivo results in vitro in promoting the raftophilic Ras to partition with membrane lipid rafts.
Inhibitors of the PAD4 enzyme that bind the inactive enzyme link this protein deiminase and the resultant arginine-to-citrulline modification to formation of neutrophil extracellular traps, highly decondensed chromatin structures with both host-defense and pathological roles.
The natural product albicidin is known to be a potential antibacterial agent, but its missing structure has stymied further studies. Structural determination and biochemical tests of NRPS domains now identify an unusual p-aminobenzoic acid–based compound.
Characterization of four enzymes involved in biosynthesis of the plant metabolite and anticancer agent noscapine completes this pathway and identifies an unusual acetyl protecting group strategy that defines the order of enzymatic steps.
PimA provides an unusual example of conformational flexibility: structural, biophysical and disulfide trapping experiments now show a glycosyltransferase involved in tuberculosis virulence undergoes a major rearrangement upon contact with membranes.
Diels-Alder chemistry is widely used for bioconjugations, and one variant of the reaction can ‘deprotect’ a small molecule via spontaneous elimination. This activation chemistry is now demonstrated on biomolecules in cells at high yields in 10 minutes.
Increasing residual helicity in the p53 transcriptional activation domain strengthened interactions with Mdm2, resulting in alterations in p53 protein dynamics, impaired transcription of target genes and failure to promote cell cycle arrest.
N6-methyladenosine (m6A) is an abundant eukaryotic RNA modification that regulates mRNA stability. Biochemical analysis and crystallographic visualization of m6A-YTHDC1 interactions establish this YTH family member as an m6A reader and explain its RNA consensus sequence selectivity.
Nonheme iron halogenases, or enzymes that perform oxidative halogenations, exist in a variety of biosynthetic pathways and modify substrates attached to carrier proteins. Biochemical evidence defines a chlorinase that breaks this rule, acting on soluble substrates.
Arylquin 1 was identified as a Par-4 secretagogue that binds the cytoskeletal intermediate filament protein vimentin and disrupts Par-4–vimentin interactions. The release of Par-4 promotes the apoptosis of cancer cells.
Alloswitch-1 is a photoswitchable modulator for mGlu5, and it is the first photoswitchable allosteric GPCR modulator. It was generated by adding the azobenzene Ar-N=N-Ar scaffold into an existing positive allosteric modulator of the receptor.
The eukaryotic Elongator complex has been assigned multiple roles in transcription and tRNA modification. In archaea, the Elp3 component is a radical SAM enzyme that catalyzes the carboxymethylation of uridine in the wobble position of tRNA.
A GPCR, the parathyroid hormone receptor, can elicit a sustained signal from internal membranes after internalization. The signal was found to be terminated by a feedback mechanism where PKA activates the proton pump v-ATPase, which acidifies endosomes.
BETP, a positive allosteric modulator of GLP-1R, a class B GPCR and an important therapeutic target for type II diabetes, covalently modifies two cysteine residues at the receptor's cytoplasmic face, where one of these enhances agonist-induced signaling. [In the version of the Table of Contents initially published, the labels for the BETP conditions were swapped in graphical abstract of the Nolte et al. article. The error has been corrected in the HTML and PDF versions of the Table of Contents.]
