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Structure-based drug discovery of cereblon (CRBN)-recruiting protein degraders has been to date challenging due to limitations with current constructs for recombinant protein expression. In this work, the authors design and validate a truncated CRBN construct, CRBNmidi, that enables crystallization and biophysical characterization of CRBN-binding ligands and degraders.

Translation elongation factor 2 (EF2) from archaea and eukaryotes contains a unique, post-translationally modified histidine residue called diphthamide, which is the target of diphtheria toxin. The biosynthesis of diphthamide involves three steps; here it is shown that the first step in the archaeon Pyrococcus horikoshii requires an unusual iron–sulphur-cluster enzyme, Dph2. It catalyses unprecedented chemistry.

Clustering of earthquake magnitudes is actively debated. Here, the authors show statistically significant magnitude clustering present in many different field and laboratory catalogs at a wide range of spatial scales (mm to 1000 km).

A biocatalytic enzyme originating from bacteria, EneIRED, facilitates amine-activated conjugate alkene reduction followed by reductive amination, efficiently preparing chiral amine diastereomers, which are commonly used in pharmaceuticals and agrochemicals. 

By enriching productive mutational paths, a Kemp eliminase that speeds up proton abstraction >10⁸-fold was developed in only five evolution rounds. Recombining it with a variant differing by 29 substitutions revealed the underlying fitness landscape.

Dissolved organic matter, the main form of aquatic organic carbon, supports the aquatic food web and regulates light penetration in lakes. This study probes the main influences on the optical properties of dissolved organic matter in a global dataset of alpine and remote lakes revealing latitudinal trends.

Here the authors use a range of approaches to examine the interplay between genetic variants linked to risk for polygenic skin diseases and transcription factors (TFs) important for skin homeostasis. The findings implicate dysregulated binding of specific TF families in risk for diverse skin diseases.

Crystal structures of the linker region of TRPML1 reveal that the luminal domain forms a tetrameric pore. Along with electrophysiology studies, this work provides insight into the mechanism of channel regulation by Ca₂₊ and H₊.

A magnetic-spectrometer-free method for electron–proton scattering data reveals a proton charge radius 2.7 standard deviations smaller than the currently accepted value from electron–proton scattering, yet consistent with other recent experiments.

Restoration of coronary blood flow after a heart attack may lead to reperfusion injury and pathologic iron deposition. Here, the authors perform magnetic susceptibility imaging showing its association with iron in a large animal model of myocardial infarction during wound healing, and showing feasibility in acute myocardial infarction patients undergoing percutaneous coronary intervention.

Aldehydes are common intermediates in enzymatic pathways, but their high reactivity can make them difficult to observe. Here, the authors study the mechanism of aldehyde deactivation in a dehydrogenase, showing a key E/Zisomerization and observing a thiohemiacetal intermediate by crystal structure analysis.

Studies in mice show that acute stress activates hyperglycaemia via activation of a medial amygdala–ventral hypothalamic circuit that controls glucose metabolic responses in the liver, independently of adrenal and pancreatic hormones.

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.

BamA carries out the essential process of folding outer membrane β-barrels in Gram-negative bacteria and is a potential antibiotic target. Here, the authors discover macrocyclic peptide inhibitors that trap BamA in distinct structural conformations.

A study leveraging transsynaptic tracing demonstrates rapid and extensive integration of human glioblastoma organoids into the mouse brain.

Biochemical and structural analysis, combined with metadynamics simulations, illustrate how a single amino acid substitution switches a β-glycosidase from a double S_N2 mechanism to a front-face S_Ni-like mechanism.

Mutations in RAS and PI3Kα drive cancer by activating the PI3K-AKT-mTOR pathway. The authors present RAS-PI3Kα structures, revealing interaction interfaces, isoform-specific differences, and a framework for designing PI3Kα-specific inhibitors.

Pentatricopeptide repeat (PPR) proteins are involved in different RNA processes, but how they recognize their target RNAs has been unclear. Now crystal structures of plant PPR protein–THA8 in complex with RNA, along with functional analyses, reveal an asymmetric THA8 dimer with RNA bound at the dimeric interface.

X-ray crystal structures of a tRNA synthetase bound to wild-type and mutant alanine tRNAs reveal the structural basis for selectivity.

Lymphocyte activation gene-3 (LAG3) is an immune checkpoint protein recently approved as a target for anti-melanoma therapy. Here, the authors solve the structure of mouse LAG3 bound to MHC-II to show that LAG3 blocks MHC-II/CD4 interactions, thereby implicating a potential mechanism of LAG3-mediated immune suppression.

Here the authors isolate monoclonal antibodies specific for Plasmodium vivax apical membrane antigen 1, and characterize the epitope of one antibody that inhibits invasion of reticulocytes and hepatocytes, and reduces liver infection in a mouse model.

There is an unmet need to improve the response to immune checkpoint blockade in patients with head and neck squamous cell carcinoma (HNSCC). Here the authors show that aberrant HER3 activation sustains the proliferation of PIK3CA wild type HNSCC cells and that HER3 inhibition increases response to PD-1 blockade in HNSCC preclinical models.

The authors determined crystal structures of the main protease (Mpro) of SARS-CoV-2 bound to substrate peptides. These structures define the substrate envelope and enable identification of sites that may be susceptible to drug resistance.

Two broadly reactive and inhibitory human monoclonal antibodies against the malaria parasite Plasmodium falciparum have been characterized, providing insights into immunity, prevention and treatment of severe malaria.

While static structures can provide insight into T cell receptor (TCR) antigen specificity, this often fails and auxiliary information is needed. Here the authors show, by focusing on an HLA-A3-bound neoantigen and its WT counterpart, the allosteric formation of a peptide-dependent dynamic gate that permits selective TCR recognition of a neoantigen.

Ebselen is an organoselenium drug that inhibits the SARS-CoV-2 main protease (M^pro). Here, the authors co-crystallised M^pro with ebselen and an ebselen derivative and observed an enzyme bound organoselenium covalent adduct in the crystal structures, which was also confirmed by mass spectrometry analysis.

Lyme disease is the leading vector-borne disease in North America and Europe, but it lacks single tests for early diagnosis. Here, authors develop a rapid and low-cost serologic test using synthetic peptides, a paper-based assay, and machine learning.

Cognitive deficits are long-lasting consequences of drug use, yet the convergent mechanism by which classes of drugs with different pharmacological properties cause similar deficits is unclear. Here authors show that phencyclidine and methamphetamine both cause glutamatergic neurons in the medial prefrontal cortex to gain a GABAergic phenotype and decrease expression of their glutamatergic phenotype, and further that suppression of drug-induced gain of GABA prevents memory deficits.

The Tousled-like kinase (TLKs) family belongs to a distinct branch of Ser/Thr kinases that exhibit the highest levels of activity during DNA replication. Here the authors present the crystal structure of the kinase domain from human TLK2 and propose an activation model for TLK2 based on biochemical and phosphoproteomics experiments.

DXPS is an important enzyme for isoprenoid synthesis in Plasmodium falciparum. Here, authors elucidate the cryo-EM structure of PfDXPS showing an N-terminal domain only present in this genus. Mutation studies show its importance in DXPS stability and activity.

A large-scale multi-ancestry whole-genome sequencing study of Alzheimer’s and related dementias identifies novel potential disease-causing variants, genetic risk and resilience factors, and offers a platform for advancing global research.

Heparan sulfate (HS) and chondroitin sulfate (CS) are different glycosaminoglycan chains that are attached to core proteins via the same linker tetrasaccharide, and it was unclear how core proteins are specifically modified with HS or CS. Here, the authors determine that the CS-initiating glycosyltransferase CSGALNACT2 is promiscuous, whereas the HS-initiating glycosyltransferase EXTL3 selects only certain core proteins for modification.

Photoinduced electron transfer forms the basis for photosynthesis and DNA repair. Ultrafast structural changes recorded for a DNA-repairing photolyase now reveal specific and directed protein motions accompanying the electron transfer.

Calcium-independent phospholipase A₂β (iPLA₂β) is involved in many physiological and pathological processes but the underlying mechanisms are largely unknown. Here, the authors present the structure of dimeric iPLA₂β, providing insights into the regulation of its activity and cellular localization.

The bacterial ABC transporter MsbA is essential for lipopolysaccharide biogenesis. Here, the authors apply native mass spectrometry, X-ray crystallography, cryo-EM and biochemical approaches to characterize the structural basis and functional roles of MsbA binding to copper and specific lipids.

Orthoreovirus σNS, essential for forming viral replication factories, has RNA chaperone activity that requires the association of σNS dimers into filamentous structures stabilized by domain-swapping interactions of the flexible N-terminal arms.

Integrating structural, biochemical, and computational methods, this work reveals metal translocation and conformational changes of a prototypical elevator-type ZIP transporter, providing insights into the metal transport mechanism.

Doudna and colleagues discuss recent advances in the targeted delivery of genome editors in vivo, offering a framework for the rational design of delivery systems.

Autotransporter proteins are localised to the bacterial surface and promote colonisation of host epithelial surfaces. Here, the authors present the crystal structure of autotransporter UpaB and show evidence for distinct binding sites for glycosaminoglycans and host fibronectin.

Dermatitis herpetiformis, a skin manifestation of the gluten-sensitive condition celiac disease, is hallmarked by autoantibody production to transglutaminase 3. Here, the authors present the 3D-structures of an autoantibody bound to transglutaminase 3 with an inhibitor mimicking a gluten-peptide substrate.