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PTPN2 (protein tyrosine phosphatase non-receptor type 2) and PTPN1 are attractive immuno-oncology targets, however, targeting PTPN2/N1 poses significant challenges. Here, the authors report the development of potent PTPN2/N1 heterobifunctional degraders and reveal biochemical and structural insights into the formation of ternary structures with cereblon E3 ligase by X-ray diffraction, cryo-EM and MD simulations.

Precise protein synthesis is achieved by tRNA modifications. Here the authors revealed that modified cytidines in tRNA^Ile use their long side chains to make additional interactions with mRNA for stable tRNA binding on the ribosome.

Terpene cyclases catalyze the formation of diverse hydrocarbon scaffolds found in terpenoids. Here, the authors report the cryptic function of class I terpene cyclases as aromatic prenyltransferases and the universality of this cryptic feature is confirmed using enzymes from different sources.

In this study, Asami et al. present the cryo-EM structure of the complex between hepatitis B virus protein and its host entry receptor NTCP, which provide a blueprint for the rational design of anti-HBV drugs targeting virus entry.

The crystal structure of the PP2A holoenzyme allows insights into assembly of the subunits, recruitment of substrate, and regulation of the enzyme by phosphorylation and methylation.

VMAT2 regulates neurotransmitter uptake into synaptic vesicles. Here, the authors determined the cryo-EM structures of VMAT2, providing a structural basis for understanding VMAT2- mediated vesicular transport of neurotransmitters.

The authors identify V-161, a compound that inhibits enterococcal Na⁺-V-ATPase and reduces VRE colonization in mice. The high-resolution structure of V-161 reveals its action on the Na+ transport pathway, offering new therapeutic insights.

Inhibitor of apoptosis BIRC2 mediates cell death and survival. Tencer et al. report the molecular mechanism underlying BIRC2 cellular localization and describe the effect of BIRC2 inhibition on the death of cancer cells and HIV-1-infected T cells.

The Mediator complex subunit MED23 contributes to transcriptional activation by the phosphorylated transcription factor Elk-1, in response to Ras-MAPK signalling. Here, the authors determine a cryo-EM structure of human MED23 with the phosphorylated activation domain of Elk-1 providing insights into the Mediator subunit-transcription factor interface.

The EMDataResource Ligand Model Challenge aimed at assessing the reliability and reproducibility of modeling ligands bound to protein and protein–nucleic acid complexes in cryo-EM maps determined at near-atomic resolution. This analysis presents the results and recommends best practices for assessing cryo-EM structures of liganded macromolecules.

The IpaH family of Shigella virulence factors are E3 ubiquitin ligases that may target host proteins. Structural and functional characterization of IpaH1.4 and IpaH9.8 reveal a unique C-terminal catalytic domain that seems to have HECT-like E3 ligase activity. Together with an accompanying publication from Zhu et al., these data suggest that the IpaH proteins constitute a new category of ubiquitin ligases.

Peptide natural product backbones are typically made ribosomally or by NRPS machinery. Exploration of pheganomycin biosynthesis defines a third hybrid model in which a grasp ligase joins an NRPS product with a ribosomally produced peptide.

Cryo-EM analyses of amyloid fibrils formed by synthetic human IAPP show an S-fold for the main polymorph, with the backbone superimposable with those of amyloid-β fibrils in antiparallel arrangement.

This study reveals how anamorelin, a superagonist targeting the ghrelin receptor, works compared to other drugs. Structural insights into ligand binding and genetic variations offer a framework for personalized therapies

The reaction mechanisms of the pyridoxal phosphate (PLP)-dependent enzymes LmbF and CcbF—involved in the biosynthesis of the antibiotic lincosamide—are characterized here. Structure–function analyses reveal structural features responsible for S-alkyl moiety diversification in lincosamides. Using structure- and calculation-based enzyme engineering, the selectivity profiles of these enzymes are designed to generate an unnatural lincosamide derivative.

The cryo-electron microscopy structures of γ-secretase bound to five anticancer clinical compounds reveal characteristic differences in recognition and suggest strategies for improved drug design.

Argonaute proteins are important in the silencing machinery with some regulatory RNAs. Here, the authors solve the structure of an argonaute protein in complex with both the guide RNA and target DNA and propose a mechanism for their recognition.

The authors show that consideration of global backbone strain enables successful de novo design of larger αβ-proteins with five- and six- stranded β-sheets flanked by α-helices.

A design pipeline is presented whereby binding proteins can be designed de novo without the need for prior information on binding hotspots or fragments from structures of complexes with binding partners.

The nuclear pore complex (NPC) is key to nucleocytoplasmic transport and is based on a stable scaffold involving multiple heptameric Y complexes. The structure of the Nup84–Nup145C–Sec13 component of the Y complex now indicates that the Nup84–Nup145C and Sec31 homotypic interface in the COPII lattice are analogous, suggesting a lattice NPC model.

Semaphorin proteins mediate signal transduction by interacting with plexin receptors; they have key roles in neuronal development and many other biological processes. Here, crystal structures are presented of the semaphorin 6A receptor-binding fragment and the plexin A2 ligand-binding fragment in their pre-signalling and signalling states. On the basis of these structures, a signalling mechanism is proposed.

An adjuvanted SARS-CoV-2 spike-ferritin nanoparticle vaccine can elicit antibodies with relatively broad sarbecovirus activity in non-human primates. Here, the authors isolate and structurally characterize several monoclonal antibodies providing insights into the targeted epitopes and broad reactivity.

Hoshino et al., engineer a human virus receptor, hACE2, and demonstrate its potential for overcoming SARS-CoV-2 mutations that otherwise hinder therapeutic interventions. Overall, the data provide insights in to the therapeutic potential of engineered receptors.

ISGylation plays a crucial role in the innate immune response and requires sequential activity of E1, E2, and E3 enzymes. Here, the authors present cyro-EM structures that reveal the molecular mechanisms underlying ISG15 activation by the E1 enzyme Uba7 and transfer to its cognate E2 enzyme UBE2L6.

An NMR structure reveals that the C terminus of the ubiquitin-conjugating enzyme Ube2w is disordered, leading to specific pairings with disordered substrates; loss of this sequence causes decreased substrate binding and ubiquitin transfer activity.

The structure of GLP-1R and its G protein in complex with the small molecule TT-OAD2 sheds light on how the TT-OAD2 agonist can activate the receptor and provides insights into the development of therapeutic agents for metabolic disorders.

Viridicatin is a fungal alkaloid. Here, the authors identify and characterize the cyclopenase that catalyzes the last step of its biosynthesis in Aspergillus nidulans, the conversion of cyclopenin to viridicatin, and find that the reaction proceeds via an unusual elimination mechanism.

FcγRs are cell-surface receptors for IgGs that play key roles in the humoral and cellular immune response to infection. Here, the authors present a high-resolution crystal structure of the hFcγRI-Fc complex to reveal the molecular mechanisms underlying the high specificity of this important immunological interaction.

LSD1-CoREST-HDAC1/2 complexes are degraded by both the drug UM171 and cancer-associated mutations in the E3 ligase KBTBD4. Here, the authors use cryo-EM to demonstrate how these mutations and UM171 similarly alter KBTBD4 to recruit HDAC1/2, illustrating a natural example of a molecular glue.

XBB.1.5 of SARS-CoV-2 is a descendant of XBB.1 and has mutations in spike and ORF8, making it more infectious to humans. Here, the authors examined in detail the differences in virological properties of the two variants.

The authors perform cryo-EM of pre-tRNA in complex with the human tRNA splicing endonuclease complex TSEN to understand the basis of pre-tRNA recognition and processing by TSEN.

JN.1 lineage is a globally dominant variant of SARS-CoV-2. Here, the authors examine structural insights into the BA.2.86 and JN.1 spike dynamics to help understand the mechanisms underlying SARS-CoV-2 infection and its neutralizing-antibody evasion.

Adenosine A₃ receptor (A₃R) plays important roles in neurons, heart, and immune cells, and is often overexpressed in tumors. Oshima et al. identify tRNA-derived i⁶A as an A₃R-selective ligand and use cryo-EM to reveal A₃R’s selectivity and activation mechanisms.

Torsins are unusual AAA + ATPases of unknown function that reside in the endoplasmic reticulum of all animals. Here the authors report that TorsinA forms tubular helical filaments with an unusual periodicity and that filamentous TorsinA directly interacts with membranes to form tubular protrusions.

Here, the authors structurally decipher how Cas12m2 protects against mobile genetic elements by tightly binding invading DNA via a unique arginine-rich cluster and its non-canonical RuvC site.

One pathway for lysine biosynthesis uses a carrier protein, LysW, to protect the substrate. LysW is now shown to mediate entry of a second substrate into the same metabolic pathway, with structural and biochemical evidence identifying an amino acid motif that determines substrate specificity.

U2AF1 binds to the 3’ splice site of introns and its mutation lead to abnormal splicing. Here the authors solve the crystal structures of wild type and pathogenic mutant U2AF1 bound to target RNA, showing that different target sequence is preferred by pathogenic mutant.

Cryo-EM structures of nucleic acid–sensing Toll-like receptors in complex with their trafficking chaperone UNC93B1, a protein that mediates TLR compartmentalization important for self versus non-self discrimination, provide insights into their interaction.

Pup is the bacterial analog of ubiquitin for targeting proteins to the proteasome. Here, the authors use cryoEM to visualize structures of the Mycobacterium tuberculosis proteasome translocating a Pup-tagged substrate.

Using cryo-electron microscopy, the authors reveal the mechanism by which perampanel-like molecules inhibit AMPA receptors. They show that the inhibitors decouple the ligand-binding domain from the ion channel after neurotransmitter binding and outcompete positive modulators.

Histamine receptor H₄R is implicated in chronic inflammatory diseases, such as asthma, arthritis, and atopic dermatitis. Here, the authors determined the first cryo-EM structure of the histamine H4 receptor, providing valuable structural insights for the design of drugs targeting H4R in chronic inflammatory diseases.

Lipid antigens have been added to the antigenic repertoire in recent years. Here, the authors have identified Mamu-B*098 as a lipopeptide antigen presenting molecule and using structural and biochemical analysis have shown that it has a different antigen binding pocket to previously analysed proteins.