Structural basis of broad-spectrum β-lactam resistance in Staphylococcus aureus. Alexander JAN, Worrall LJ, Hu J, Vuckovic M, Satishkumar N, Poon R, Sobhanifar S, Rosell FI, Jenkins J, Chiang D, Mosimann WA, Chambers HF, Paetzel M, Chatterjee SS, Strynadka NCJ. Nature. 2023 Jan;613(7943):375–82.
Chemoproteomic identification of CO2-dependent lysine carboxylation in proteins. King DT, Zhu S, Hardie DB, Serrano-Negrón JE, Madden Z, Kolappan S, Vocadlo DJ. Nat Chem Biol. 2022 Jul;18(7):782–91.
Biochemical and structural characterization of Rab3GAP reveals insights into Rab18 nucleotide exchange activity. Fairlie GMJ, Nguyen KM, Nam SE, Shaw AL, Parson MAH, Shariati HR, Wang X, Jenkins ML, Gong M, Burke JE, Yip CK. Nat Commun. 2025 Jan 8;16(1):479.
A heme-dependent enzyme forms the hydrazine in the antibiotic negamycin. Wang M, Wei ZW, Ryan KS. Nat Chem Biol. 2025 Jul;21(7):1012–20.
The 60-year evolution of lipid nanoparticles for nucleic acid delivery. Cullis PR, Felgner PL. Nat Rev Drug Discov. 2024 Sep;23(9):709–22.
Cryo-EM structures of ryanodine receptors and diamide insecticides reveal the mechanisms of selectivity and resistance. Lin L, Wang C, Wang W, Jiang H, Murayama T, Kobayashi T, Hadiatullah H, Chen YS, Wu S, Wang Y, Korza H, Gu Y, Zhang Y, Du J, Van Petegem F, Yuchi Z. Nat Commun. 2024 Oct 20;15(1):9056.
Delivery vehicle and route of administration influences self-amplifying RNA biodistribution, expression kinetics, and reactogenicity. Bathula NV, Friesen JJ, Casmil IC, Wayne CJ, Liao S, Soriano SKV, Ho CH, Strumpel A, Blakney AK. J Control Release Off J Control Release Soc. 2024 Oct;374:28–38.
Cell envelope diversity and evolution across the bacterial tree of life. Hashimi A, Tocheva EI. Nat Microbiol. 2024 Oct;9(10):2475–87.
A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic. Shapira T, Monreal IA, Dion SP, Buchholz DW, Imbiakha B, Olmstead AD, Jager M, Désilets A, Gao G, Martins M, Vandal T, Thompson CAH, Chin A, Rees WD, Steiner T, Nabi IR, Marsault E, Sahler J, Diel DG, Van de Walle GR, August A, Whittaker GR, Boudreault PL, Leduc R, Aguilar HC, Jean F. Nature. 2022 May;605(7909):340–8.
Extended List of Recent Work from ASTRID
- The KCNQ1 (Kv7.1) potassium ion (K^(+)) channel plays a critical role in cardiac repolarization, while loss- or gain-of-function mutations increase the risk of life-threatening arrythmias and sudden death. Like many channels, KCNQ1 exhibits state-dependent pharmacological properties with inhibitors such as UCL2077 displaying higher potency for intermediate over activated states. Here, we report cryo-EM structures and […]
- Lipid nanoparticles (LNPs) are the leading platform for delivery of RNA-based therapeutics. There is considerable interest in optimizing the transfection potency of these systems. Standard formulation protocols involve mixing lipids in ethanol with a buffer containing mRNA at pH 4, followed by dialysis against a pH 7.4 saline buffer to remove ethanol and raise the […]
- The cardiac calcium channel Ca(v)1.2 is essential for embryonic development, cardiac excitation-contraction coupling, and the "Fight or Flight" response. Regulation of Ca(v)1.2 by protein kinase A (PKA) phosphorylation is critical to this process, though the underlying mechanism remains contentious. We previously identified serine 1458 (S1458) in the proximal C-terminus of the human Ca(v)1.2 as essential […]
- Retinal membrane guanylyl cyclase (RetGC) regulated by guanylyl cyclase activating proteins (GCAPs) enables photoreceptor light sensitivity by producing cGMP to open cyclic nucleotide gated channels. The quaternary structure of the RetGC:GCAP complex remains unresolved. In this study, we conducted site-directed mutagenesis of RetGC1 based on the RetGC1:GCAP1 complex structure generated using AlphaFold 3 in order […]
- No abstract
- Hybrid multiphase liposomes containing coexisting aqueous and oil-rich internal compartments were used as a model system to investigate how lipid assemblies respond to externally applied mechanical stress. A magneto-mechanical system was developed in which a miniature ball-bearing, driven by a rotating magnetic field, generated localized rolling-contact shear and confinement conditions within an enclosed fluid chamber, […]
- Many genetic neurological diseases are caused by toxic gain-of-function of a mutant protein or loss-of-function of a wild-type protein. Treatment of these disorders may be feasible using gene therapy, which requires delivering therapeutic agents to affected brain regions and cells. Lipid nanoparticles (LNPs) have significant potential for this purpose: the clinical safety and efficacy of […]
- The pathogenic yeast Cryptococcus neoformans causes life-threatening meningoencephalitis in individuals with compromised immune systems. The ability of the fungus to cause disease depends on key cell-surface features, such as a polysaccharide capsule that protects it from the mammalian immune system. However, the mechanisms by which C. neoformans traffics polysaccharide capsule, melanin, and other materials to […]
- Primary idiopathic hyperhidrosis (PIH) is a poorly understood disorder characterized by excessive sweating. We identify a genetically defined subset of PIH associated with rare coding changes in voltage-gated Na^(+) (Na(V)) channels. Whole-exome sequencing of hereditary PIH families revealed gene-level enrichment within the Na(V) channel family, with SCN10A (Na(V)1.8) most strongly implicated. A knock-in mouse carrying […]
- Self-amplifying RNA (saRNA) is an emerging RNA therapeutic modality that can facilitate higher magnitude and more durable protein expression at substantially lower doses than nonreplicating mRNA. Unlike conventional messenger RNA (mRNA), alphavirus-derived saRNA must support a replicase-driven RNA amplification step in addition to translation, raising the possibility that transgene coding sequences impose sequence-level constraints on […]
- Bridge-like lipid transfer proteins (BLTPs) play fundamental roles in cellular lipid redistribution between organellar membranes. They comprise bridge domains spanning organelles at contact sites that allow lipids to transit through the cytosol between adjacent membranes. The assembly of BLTPs into complexes with adaptor proteins enables lipid transfer. To address the mechanisms underlying the assembly and […]
- MR1 is a non-polymorphic, ubiquitously expressed, MHC class I-like antigen-presenting molecule that presents small-molecule metabolites to T cells. Studies have shown that MR1 plays a role in microbial infection, inflammation, and tumor immunity. The antigens it presents include metabolites of microbial and self-origin as well as small-molecule drugs and form stable complexes with MR1 that […]
- mRNA vaccines represent a transformative advance in vaccinology, combining rapid development timelines, scalable manufacturing, and strong immunogenicity with a favourable safety profile. Global deployment of mRNA vaccines during the COVID-19 pandemic provided an unprecedented real-world evaluation of this platform, with billions of doses administered across diverse populations. In this Review, we critically examine the safety […]
- Auxiliary β1 subunits play an important role in modulating voltage-gated Na+ (NaV) channel gating, thereby influencing their voltage-dependent behavior and overall function. Here, we examine β1 modulation of human NaV1.6 channels expressed in Xenopus laevis oocytes and identify a glutamate in the extracellular S3-S4 loop of domain IV (VSDIV; E1607) as a key determinant of […]
- The armadillo repeat protein ARMH3 regulates the activity and localization of the Golgi resident lipid kinase phosphatidylinositol 4 kinase IIIβ (PI4KB) and the Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1 (GBF1) that activates Arf1. ARMH3 localizes to the trans-Golgi network (TGN) via the GTPase Arl5. We used hydrogen deuterium exchange mass spectrometry (HDX-MS) and […]
- The unambiguous identification of protein O-GlcNAcylation remains challenging because O-GlcNAc and O-GalNAc are isobaric and produce nearly indistinguishable fragmentation patterns under standard higher-energy collisional dissociation (HCD) conditions. Here, we report a chemoenzymatic strategy that enables selective detection of O-GlcNAc through enzymatic deacetylation. We show that the Cyclobacterium marinum deacetylase CmCBDA uniquely and efficiently converts beta-O-GlcNAc, […]
- No abstract
- Increasing threats of viral disease underscore the urgent need for broad-spectrum antiviral drugs (BSADs). Host proteins utilized by human pathogenic viruses are key BSAD targets. The vacuolar-type H^(+)-ATPase (V-ATPase) has been identified as a proviral factor for most pH-dependent enveloped viruses classified as pandemic threats. We report here the discovery of cladoniamide A (CA), a […]
- Lipid nanoparticles (LNP) are currently the most advanced delivery platform for mRNA therapeutics. To reach extrahepatic tissues, it is beneficial to engineer LNP-mRNA systems with improved stability and prolonged blood circulation lifetimes. In previous work we have shown that LNP-mRNA systems with liposomal morphology that contain egg sphingomyelin (ESM) can exhibit longer circulation lifetimes and […]
- The direct binding of cAMP to the hyperpolarization-activated cyclic nucleotide-gated channel form 4 (HCN4) protein contributes to autonomic modulation of heart rate. Here, we determine affinity for binding of cyclic nucleotides directly to the cytosolic C-terminus of the HCN4 channel of three disease-linked mutations that are found in the C-linker of the C-terminus, which attaches […]