ACS DIVISION OF BIOLOGICAL CHEMISTRY

November 13th, 2019 by Tingting Liu, Qingsong Sun, Yong Liu, Shan Cen, Quan Zhang

Interferons inhibit viruses by inducing antiviral protein expression. One of the interferon-induced antiviral proteins, human Moloney leukemia virus 10 (MOV10), a superfamily 1 RNA helicase, has been shown to inhibit retroviruses and several RNA viruses. However, it remains undetermined whether MOV10 also inhibits DNA viruses, including hepatitis B virus (HBV). Here, we report that MOV10 dramatically reduces the levels of intracellular HBV DNA, resulting in significant inhibition of both the HBV experimental strain and the clinical isolates. Mechanistic experiments revealed that MOV10 interacts with HBV RNA and blocks the early step of viral reverse transcription, thereby impairing viral DNA synthesis, without affecting viral gene expression and pregenomic RNA encapsidation. Moreover, mutation of the helicase domain of MOV10 caused loss of binding to HBV RNA and of the anti-HBV activity. Together, our results indicate that MOV10 restricts HBV replication, insights that may open new avenues to the development of anti-HBV therapeutics.

November 7th, 2019 by Andrew R. Osborn and Taifo Mahmud*

November 4th, 2019 by Jongmin Kim

Nature Chemical Biology, Published online: 04 November 2019; doi:10.1038/s41589-019-0388-1

Two programmable riboregulator systems, based on toehold and three-way junction RNA motifs, were designed and validated as robust translational repressors in cells and applied for the construction of logic gates.

November 4th, 2019 by Luz S. Gonzalez-Delgado

Nature Chemical Biology, Published online: 04 November 2019; doi:10.1038/s41589-019-0393-4

A structural look at the interaction between the SH3b domain of the peptidoglycan endopeptidase lysostaphin and the target for its antistaphylococcal activity, peptidoglycan, reveals a mechanism of bacterial cell wall binding.

November 4th, 2019 by Tyler B. Faust

Nature Chemical Biology, Published online: 04 November 2019; doi:10.1038/s41589-019-0378-3

Cryo-EM and crystal structural analysis of DDB1–DCAF15–DDA1 in complex with E7820 and RBM39 reveal that aryl-sulfonamides reshape the surface of the cullin RING ligase substrate receptor DCAF15 to bind and degrade the splicing factor RBM39.

October 31st, 2019 by Edward Marschall, Max J. Cryle, Julien Tailhades

Since the discovery of vancomycin in the 1950s, the glycopeptide antibiotics (GPAs) have been of great interest to the scientific community. These non-ribosomally biosynthesized peptides are highly crosslinked, often glycosylated, and inhibit bacterial cell wall assembly by interfering with peptidoglycan synthesis. Interest in glycopeptide antibiotics covers many scientific disciplines, due to their challenging total syntheses, complex biosynthesis pathways, mechanism of action, and high potency. After intense efforts, early enthusiasm has given way to a recognition of the challenges in chemically synthesizing GPAs and of the effort needed to study and modify GPA-producing strains to prepare new GPAs in order to address the increasing threat of microbial antibiotic resistance. Although preparation of GPAs, either by modifying the pendant groups such as saccharides or by functionalizing the N- or C-terminal moieties are readily achievable, the peptide core of these molecules – the GPA aglycone – remains highly challenging to modify. This review aims to present a comprehensive analysis of the results of GPA modification obtained with the three major approaches developed to date: in vivo strain manipulation, total chemical synthesis, and chemoenzymatic synthesis methods.

October 31st, 2019 by Hon Cheung Lee, Yong Juan Zhao

Cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) are two structurally distinct messengers that mobilize the endoplasmic and endo-lysosomal Ca2+-stores, respectively. Both are synthesized by CD38 molecule (CD38), which has long been thought to be a type II membrane protein whose catalytic domain, intriguingly, faces to the outside of the cell. Accordingly, for more than 20 years it has remained unresolved how CD38 can use cytosolic substrates such as NAD and NADP to produce messengers that target intracellular Ca2+-stores. The discovery of type III CD38 whose catalytic domain faces the cytosol has now begun to clarify this topological conundrum. This article reviews the ideas and clues leading to the discovery of the type III CD38; highlights an innovative approach for uncovering its natural existence, and discusses the regulators of its activity, folding and degradation. We also review the compartmentalization of cADPR and NAADP biogenesis. We further discuss the possible mechanisms that promote type III CD38 expression and appraise a proposal of a Ca2+-signaling mechanism based on substrate limitation and product translocation. The surprising finding of another enzyme that produces cADPR and NAADP, sterile alpha and TIR motif containing1 (SARM1), is described. SARM1 regulates axonal degeneration and has no sequence similarity with CD38, but can catalyze the same set of multi-reactions and has the same cytosolic orientation as the type III CD38. The intriguing finding that SARM1 is activated by nicotinamide mononucleotide to produce cADPR and NAADP suggests that it may function as a regulated Ca2+-signaling enzyme like CD38.

October 31st, 2019 by Clare L Hawkins, Michael J Davies

Exposure of biological molecules to oxidants is inevitable and therefore commonplace. Oxidative stress in cells arises from both external agents and endogenous processes that generate reactive species, either purposely (e.g. during pathogen killing or enzymatic reactions) or accidently (e.g. exposure to radiation, pollutants, drugs, or chemicals). As proteins are highly abundant and react rapidly with many oxidants, they are highly susceptible to, and major targets of, oxidative damage. This can result in changes to protein structure, function, and turnover and to loss or (occasional) gain of activity. Accumulation of oxidatively modified proteins, due to either increased generation or decreased removal, has been associated with both aging and multiple diseases. Different oxidants generate a broad, and sometimes characteristic, spectrum of post-translational modifications. The kinetics (rates) of damage formation also vary dramatically. There is a pressing need for reliable and robust methods that can detect, identify, and quantify the products formed on amino acids, peptides, and proteins, especially in complex systems. This review summarizes several advances in our understanding of this complex chemistry and highlights methods that are available to detect oxidative modifications—at the amino acid, peptide, or protein level—and their nature, quantity, and position within a peptide sequence. Although considerable progress has been made in the development and application of new techniques, it is clear that further development is required to fully assess the relative importance of protein oxidation and to determine whether an oxidation is a cause, or merely a consequence, of injurious processes.

October 28th, 2019 by Shuai Wang

Nature Chemical Biology, Published online: 28 October 2019; doi:10.1038/s41589-019-0379-2

Small molecules that achieve selective PARP1 degradation were developed that block both the catalytic activity and scaffolding effects of PARP1, enabling the decoupling of PARP1 inhibition and PARP1 trapping.

October 28th, 2019 by Zhenhua Shao

Nature Chemical Biology, Published online: 28 October 2019; doi:10.1038/s41589-019-0387-2

A crystal structure of the GPCR target of endocannabinoid signaling lipids and drugs, CB1, bound to a negative allosteric modulator (NAM) and an agonist, shows that the NAM binds to a membrane-embedded site reminiscent of the binding site of cholesterol.