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Botulinum neurotoxin B binds to two neuronal surface receptors, synaptotagmin II and ganglioside receptor GD1a. Berntsson et al.present the crystal structure of botulinum neurotoxin B in complex with both receptor proteins, demonstrating independent binding.

There are seven well-established types of Botulinum neurotoxins (BoNTs). Here the authors report the identification and characterization of a new type of BoNT—BoNT/X—which cleaves a different site on canonical BoNTs substrates and targets SNARE family members not cleaved by known BoNTs.

Ribonucleotide reductase (RNR) is an essential enzyme that catalyzes the synthesis of DNA building blocks. Here, the authors present the cryo-EM structure and mechanism of action of NrdR, the RNR-specific repressor, that controls transcription of RNR genes in bacteria.

Nucleoside analogs (NNA), such as acyclovir (ACV) and ganciclovir (GCV), are widely used as anti-virals to treat herpes virus infection. Here, Nishii et al. show that diphosphatase NUDT15 hydrolyzes ACV and GCV, therewith reducing NNA activity in vitro and link NUDT15 variation to inter-patient variability in ACV and GCV therapeutic effects.

The pyruvate dehydrogenase complex (PDHc) is a large multienzyme complex that converts pyruvate into acetyl-coenzyme A and in E. coli the core of the PDHc is formed by 24 copies of dihydrolipoyl transacetylase. Here, the authors present the cryo-EM structure of the E. coli dihydrolipoyl transacetylase 24-mer core in a native resting state including lipoyl domains, and discuss the mechanism of substrate shuttling by the lipoyl domains.

So far identified clostridial neurotoxins target vertebrates. Here, Contreras et al. isolate the clostridial-like neurotoxin PMP1 from Paraclostridium bifermentans strains and show that it selectively targets anopheline mosquitoes by targeting mosquito syntaxin.

Fragment-based drug design is an efficient yet challenging approach for developing therapeutics. Here, the authors employ structure-based docking screens of vast fragment libraries to identify inhibitors of 8-oxoguanine DNA glycosylase, a difficult drug target implicated in cancer and inflammation.

Cellular target engagement technologies enable quantification of intracellular drug binding, but the simultaneous assessment of drug-associated phenotypes is challenging. Here, the authors develop CeTEAM (cellular target engagement by accumulation of mutant), a platform that can simultaneously evaluate drug-target interactions and phenotypic responses for holistic assessment of drug pharmacology using conditionally stabilized drug biosensors.

Dysfunctional redox regulation in cancer can damage dNTPs so inhibiting dNTP pool sanitizing enzymes, such as MTH1, is a potential cancer treatment. Here, Carter et al.characterize MTH2 (NUDT15) and show that it is not a dNTP sanitizer, and so is unlikely to influence the efficacy of MTH1 inhibitors.

Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.

Humans are less sensitive to the therapeutic effects of botulinum neurotoxin B (BoNT/B) than the animal models it is tested on due to differences between the human and the mouse receptors. Here, the authors engineer BoNT/B to improve its affinity to human receptors and enhance its therapeutic efficacy.

Botulinum neurotoxins (BoNTs) are thought to require complex gangliosides, a group of glycosphingolipids, as essential co-receptors to target neurons. Here, the authors show that BoNT/DC represents an exception to this rule and that an extended loop in BoNT/DC penetrates directly into neuronal membranes.

Epitope tags are widely used in various applications, but often lack versatility. Here, the authors introduce a small, alpha helical tag, which is recognized by a high affinity nanobody and can be used in a range of different applications, from protein purification to super-resolution imaging and in vivo detection of proteins.

TH1760 is a first-in-class, potent, selective and cell-active inhibitor against human NUDT15, which sensitizes cells to 6-thioguanine treatment. TH1760 represents a valuable tool for deciphering the enigmatic functions of NUDT15.

IMPDH and GMPR have similar active sites, but their reactions cause opposite effects on the guanine nucleotide pool. Biochemical and crystallographic evidence point to cofactor conformation as distinguishing the two reaction mechanisms and demonstrate that GMPR can substitute for IMPDH, prompting further investigations of this metabolic cycle.

In order to find a general treatment for cancer, this study found that MTH1 activity is essential for the survival of transformed cells, and isolated two small-molecule inhibitors of MTH1, TH287 and TH588 — in the presence of these inhibitors, damaged nucleotides are incorporated into DNA only in cancer cells, causing cytotoxicity and eliciting a beneficial response in patient-derived mouse xenograft models.

The NUDIX hydrolases are known to be involved in several cellular processes and diseases, such as cancer, but remain poorly characterized as a family. Here, the authors provide a comprehensive analysis of the structural, biochemical, and expression properties of 18 human NUDIX proteins, and begin to address their functional inter-relationships.

NUDIX hydrolases are an important family of nucleotide-metabolizing enzymes. Here, the authors identify potent, small molecule inhibitors of NUDT5, which is implicated in ADP-ribose and 8-oxo-guanine metabolism, and confirm its role in gene regulation and proliferation in breast cancer cells.

Botulinum neurotoxins (BoNT) are the causative agents of botulism but are also widely used to treat neurological disorders, however, the development of variants with enhanced therapeutic potential remains challenging. Here, the authors identify BoNT/A mutants with enhanced ganglioside-binding and improved potency, and elucidate the molecular mechanism underlying the increased affinity and altered ganglioside selectivity.

Botulinum neurotoxins (BoNTs) are a family of protein toxins produced by clostridial bacteria that cause muscle paralysis, and exhibit structural and functional diversity within the BoNTs family. Here, the authors report the cryo-EM structure complex of a newly identified serotype BoNT/X with their partner protein NTNH/X and reveal the complex’s pH-dependent stability and receptor-binding properties.