Structure of small HBV surface antigen reveals mechanism of dimer formation
Related Articles
Structural insights into tecovirimat antiviral activity and poxvirus resistance
Mpox is a zoonotic disease endemic to Central and West Africa. Since 2022, two human-adapted monkeypox virus (MPXV) strains have caused large outbreaks outside these regions. Tecovirimat is the most widely used drug to treat mpox. It blocks viral egress by targeting the viral phospholipase F13; however, the structural details are unknown, and mutations in the F13 gene can result in resistance against tecovirimat, raising public health concerns. Here we report the structure of an F13 homodimer using X-ray crystallography, both alone (2.1 Å) and in complex with tecovirimat (2.6 Å). Combined with molecular dynamics simulations and dimerization assays, we show that tecovirimat acts as a molecular glue that promotes dimerization of the phospholipase. Tecovirimat resistance mutations identified in clinical MPXV isolates map to the F13 dimer interface and prevent drug-induced dimerization in solution and in cells. These findings explain how tecovirimat works, allow for better monitoring of resistant MPXV strains and pave the way for developing more potent and resilient therapeutics.
Cryo-EM structure of PML RBCC dimer reveals CC-mediated octopus-like nuclear body assembly mechanism
Promyelocytic leukemia protein (PML) nuclear bodies (NBs) are essential in regulating tumor suppression, antiviral response, inflammation, metabolism, aging, and other important life processes. The re-assembly of PML NBs might lead to an ~100% cure of acute promyelocytic leukemia. However, until now, the molecular mechanism underpinning PML NB biogenesis remains elusive due to the lack of structural information. In this study, we present the cryo-electron microscopy (cryo-EM) structure of the PML dimer at an overall resolution of 5.3 Å, encompassing the RING, B-box1/2 and part of the coiled-coil (RBCC) domains. The integrated approach, combining crosslinking and mass spectrometry (XL-MS) and functional analyses, enabled us to observe a unique folding event within the RBCC domains. The RING and B-box1/2 domains fold around the α3 helix, and the α6 helix serves as a pivotal interface for PML dimerization. More importantly, further characterizations of the cryo-EM structure in conjugation with AlphaFold2 prediction, XL-MS, and NB formation assays, help unveil an unprecedented octopus-like mechanism in NB assembly, wherein each CC helix of a PML dimer (PML dimer A) interacts with a CC helix from a neighboring PML dimer (PML dimer B) in an anti-parallel configuration, ultimately leading to the formation of a 2 µm membrane-less subcellular organelle.
Alleviating NIR-II emission quenching in ring-fused fluorophore via manipulating dimer populations for superior fluorescence imaging
Emission quenching resulting from fluorophore aggregation has long been a significant challenge in optimizing emission-based technologies, such as fluorescence imaging and optoelectronic devices. Alleviating this quenching in aggregates is crucial, yet progress is impeded by the limited understanding of the nature and impact of aggregates on emission. Here, we elucidate the critical role of dimeric aggregate (dimer) in alleviating second near-infrared (NIR-II, 900-1700 nm) emission quenching from ring-fused fluorophore 4F for superior fluorescence imaging. Spectral decomposition and molecular dynamics simulations demonstrate the predominance of dimer populations in 4F aggregates. Notably, dimers exhibit significantly weaker emission but intense intermolecular nonradiative (interNR) decay compared to monomers, as demonstrated by ultrafast spectra and quantum calculation. Therefore, the predominant population of dimers with weak emission and pronounced interNR feature underlies the emission quenching in 4F aggregates. This discovery guides the preparation of ultrabright NIR-II 4F nanofluorophore (4F NP3s) by decreasing dimer populations, which show 5-fold greater NIR-II brightness than indocyanine green, enabling superior resolution in visualizing blood vessels. This work offers valuable insights into aggregation-caused quenching, with broad implications extending far beyond NIR-II fluorescence imaging.
Edge states with hidden topology in spinner lattices
Symmetries – whether explicit, latent, or hidden – are fundamental to understanding topological materials. This work introduces a prototypical spring-mass model that extends beyond established canonical models, revealing topological edge states with distinct profiles at opposite edges. These edge states originate from hidden symmetries that become apparent only in deformation coordinates, as opposed to the conventional displacement coordinates used for bulk-boundary correspondence. Our model, realized through the intricate connectivity of a spinner chain, demonstrates experimentally distinct edge states at opposite ends. By extending this framework to two dimensions, we explore the conditions required for such edge waves and their hidden symmetry in deformation coordinates. We also show that these edge states are robust against disorders that respect the hidden symmetry. This research paves the way for advanced material designs with tailored boundary conditions and edge state profiles, offering potential applications in fields such as photonics, acoustics, and mechanical metamaterials.
Filamentation activates bacterial Avs5 antiviral protein
Bacterial antiviral STANDs (Avs) are evolutionarily related to the nucleotide-binding oligomerization domain (NOD)-like receptors widely distributed in immune systems across animals and plants. EfAvs5, a type 5 Avs from Escherichia fergusonii, contains an N-terminal SIR2 effector domain, a NOD, and a C-terminal sensor domain, conferring protection against diverse phage invasions. Despite the established roles of SIR2 and STAND in prokaryotic and eukaryotic immunity, the mechanism underlying their collaboration remains unclear. Here we present cryo-EM structures of EfAvs5 filaments, elucidating the mechanisms of dimerization, filamentation, filament bundling, ATP binding, and NAD+ hydrolysis, all of which are crucial for anti-phage defense. The SIR2 and NOD domains engage in intra- and inter-dimer interaction to form an individual filament, while the outward C-terminal sensor domains contribute to bundle formation. Filamentation potentially stabilizes the dimeric SIR2 configuration, thereby activating the NADase activity of EfAvs5. Furthermore, we identify the nucleotide kinase gp1.7 of phage T7 as an activator of EfAvs5, demonstrating its ability to induce filamentation and NADase activity. Together, we uncover the filament assembly of Avs5 as a unique mechanism to switch enzyme activities and perform anti-phage defenses.
Responses