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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.]
Drug-resistance mutations provide a classical means to identify biological targets of small molecules. A combination of next-generation DNA sequencing with CRISPR-Cas9 genome editing confirms the targets of 6-thioguanine and triptolide and offers a general approach for target identification in cells.
Finding the biological targets of small molecules remains an important challenge in chemical biology and drug discovery. A method involving high-throughput sequencing, mutational analysis and clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 genome editing identifies the targets and potential modes of compound resistance for two anticancer agents.
Genetic code reprogramming has generally focused on changing the translation step of protein expression, altering what each codon specifies. Mutations in the peptidyl transferase center, along with compensatory mutations in the C-termini of tRNAs, now provide an alternate method to create fully orthogonal ribosomes.
Carbonates exist in a few natural products, but their biosynthetic origins have been unclear. Genetic and biochemical characterization of a flavin-dependent monooxygenase from the cytochalasin cluster now demonstrates conversion of a ketone into a carbonate prior to other tailoring steps.
Ether lipids are found in both mammals and bacteria, but only the mammalian biosynthesis pathway is known. Bioinformatic, biochemical and genetic evidence now locate the bacterial pathway within a multigene cluster that includes the four-domain, PKS-like ElbD.
The transplantation of residues from a selective to a nonselective haloalkane dehalogenase yields the correct active site geometry but not function. Computational and biophysical results explain this disparity, showing that the dynamics and hydration of the engineered protein match its parent, not its target.
Lasso peptides are antimicrobial bacterial peptides that hijack outer membrane siderophores to kill target cells. The structural and biochemical basis of antimicrobial lasso peptide MccJ25 binding to siderophore FhuA explains why these peptides have a narrow range of target species.
Heparin analogs can serve as potent anticoagulants, but heterogeneous structures in some preparations and lack of antidote for others can complicate treatments. A chemoenzymatic method that prevents reversible epimerization now enables reversible application of defined constructs in cells and mice.
Translational reprogramming, which enables site-specific incorporation of non-natural amino acids into proteins, offers practical tools for studying protein function but also provides insights into the genetic code. Bacteriophages engineered with a 21-amino-acid genetic code make use of the additional noncanonical amino acid during in vitro evolution.
