Genome packaging is a fundamental process in a viral life cycle and a prime target of antiviral drugs. Herpesviruses use an ATP-driven packaging motor/terminase complex to translocate and cleave ...concatemeric dsDNA into procapsids but its molecular architecture and mechanism are unknown. We report atomic structures of a herpesvirus hexameric terminase complex in both the apo and ADP•BeF3-bound states. Each subunit of the hexameric ring comprises three components—the ATPase/terminase pUL15 and two regulator/fixer proteins, pUL28 and pUL33—unlike bacteriophage terminases. Distal to the nuclease domains, six ATPase domains form a central channel with conserved basic-patches conducive to DNA binding and trans-acting arginine fingers are essential to ATP hydrolysis and sequential DNA translocation. Rearrangement of the nuclease domains mediated by regulatory domains converts DNA translocation mode to cleavage mode. Our structures favor a sequential revolution model for DNA translocation and suggest mechanisms for concerted domain rearrangements leading to DNA cleavage.
Hepatitis A virus (HAV) remains enigmatic, despite 1.4 million cases worldwide annually. It differs radically from other picornaviruses, existing in an enveloped form and being unusually stable, both ...genetically and physically, but has proved difficult to study. Here we report high-resolution X-ray structures for the mature virus and the empty particle. The structures of the two particles are indistinguishable, apart from some disorder on the inside of the empty particle. The full virus contains the small viral protein VP4, whereas the empty particle harbours only the uncleaved precursor, VP0. The smooth particle surface is devoid of depressions that might correspond to receptor-binding sites. Peptide scanning data extend the previously reported VP3 antigenic site, while structure-based predictions suggest further epitopes. HAV contains no pocket factor and can withstand remarkably high temperature and low pH, and empty particles are even more robust than full particles. The virus probably uncoats via a novel mechanism, being assembled differently to other picornaviruses. It utilizes a VP2 'domain swap' characteristic of insect picorna-like viruses, and structure-based phylogenetic analysis places HAV between typical picornaviruses and the insect viruses. The enigmatic properties of HAV may reflect its position as a link between 'modern' picornaviruses and the more 'primitive' precursor insect viruses; for instance, HAV retains the ability to move from cell-to-cell by transcytosis.
Human ATP‐binding cassette transporter 6 of subfamily B (ABCB6) is an ABC transporter involved in the translocation toxic metals and anti‐cancer drugs. Using cryo‐electron microscopy, we determined ...the molecular structure of full‐length ABCB6 in an apo state. The structure of ABCB6 unravels the architecture of a full‐length ABCB transporter that harbors two N‐terminal transmembrane domains which is indispensable for its ATPase activity in our in vitro assay. A slit‐like substrate binding pocket of ABCB6 may accommodate the planar shape of porphyrins, and the existence of a secondary cavity near the mitochondrial intermembrane space side would further facilitate substrate release. Furthermore, the ATPase activity of ABCB6 stimulated with a variety of porphyrin substrates showed different profiles in the presence of glutathione (GSH), suggesting the action of a distinct substrate translocation mechanism depending on the use of GSH as a cofactor.
Nanostructured metal phosphides are very attractive materials in energy storage and conversion, but their applications are severely limited by complicated preparation steps, harsh conditions and ...large excess of highly toxic phosphorus source. Here we develop a highly efficient one-step method to synthesize Sn
4
P
3
nanostructure based on simultaneous reduction of SnCl4 and PCl
3
on mechanically activated Na surface and
in situ
phosphorization. The low-toxic PCl
3
displays a very high phosphorizing efficiency (100%). Furthermore, this simple method is powerful to control phosphide size. Ultrafine Sn
4
P
3
nanocrystals (< 5 nm) supported on carbon sheets (Sn
4
P
3
/C) are obtained, which is due to the unique bottom-up surface-limited reaction. As the anode material for sodium/lithium ion batteries (SIBs/LIBs), the Sn
4
P
3
/C shows profound sodiation/lithiation extents, good phase-conversion reversibility, excellent rate performance and long cycling stability, retaining high capacities of 420 mAh/g for SIBs and 760 mAh/g for LIBs even after 400 cycles at 1.0 A/g. Combining simple and efficient preparation, low-toxic and high-efficiency phosphorus source and good control of nanosize, this method is very promising for low-cost and scalable preparation of high-performance Sn
4
P
3
anode.
Although several different flaviviruses may cause encephalitis, Japanese encephalitis virus is the most significant, being responsible for thousands of deaths each year in Asia. The structural and ...molecular basis of this encephalitis is not fully understood. Here, we report the cryo-electron microscopy structure of mature Japanese encephalitis virus at near-atomic resolution, which reveals an unusual "hole" on the surface, surrounded by five encephalitic-specific motifs implicated in receptor binding. Glu138 of E, which is highly conserved in encephalitic flaviviruses, maps onto one of these motifs and is essential for binding to neuroblastoma cells, with the E138K mutation abrogating the neurovirulence and neuroinvasiveness of Japanese encephalitis virus in mice. We also identify structural elements modulating viral stability, notably Gln264 of E, which, when replaced by His264 strengthens a hydrogen-bonding network, leading to a more stable virus. These studies unveil determinants of neurovirulence and stability in Japanese encephalitis virus, opening up new avenues for therapeutic interventions against neurotropic flaviviruses.Japanese encephalitis virus (JEV) is a Flavivirus responsible for thousands of deaths every year for which there are no specific anti-virals. Here, Wang et al. report the cryo-EM structure of mature JEV at near-atomic resolution and identify structural elements that modulate stability and virulence.
Coxsackievirus A10 (CVA10), a human type-A Enterovirus (HEV-A), can cause diseases ranging from hand-foot-and-mouth disease to polio-myelitis-like disease. CVA10, together with some other HEV-As, ...utilizing the molecule KREMEN1 as an entry receptor, constitutes a KREMEN1-dependent subgroup within HEV-As. Currently, there is no vaccine or antiviral therapy available for treating diseases caused by CVA10. The atomic-resolution structure of the CVA10 virion, which is within the KREMEN1-dependent subgroup, shows significant conformational differences in the putative receptor binding sites and serotype-specific epitopes, when compared to the SCARB2-dependent subgroup of HEV-A, such as EV71, highlighting specific differences between the sub-groups. We also report two expanded structures of CVA10, an empty particle and uncoating intermediate at atomic resolution, as well as a medium-resolution genome structure reconstructed using a symmetry-mismatch method. Structural comparisons coupled with previous results, reveal an ordered signal transmission process for enterovirus uncoating, converting exo-genetic receptor-attachment inputs into a generic RNA release mechanism.
Enterovirus 71 (EV71) is a major agent of hand, foot and mouth disease in children that can cause severe central nervous system disease and death. No vaccine or antiviral therapy is available. ...High-resolution structural analysis of the mature virus and natural empty particles shows that the mature virus is structurally similar to other enteroviruses. In contrast, the empty particles are markedly expanded and resemble elusive enterovirus-uncoating intermediates not previously characterized in atomic detail. Hydrophobic pockets in the EV71 capsid are collapsed in this expanded particle, providing a detailed explanation of the mechanism for receptor-binding triggered virus uncoating. These structures provide a model for enterovirus uncoating in which the VP1 GH loop acts as an adaptor-sensor for cellular receptor attachment, converting heterologous inputs to a generic uncoating mechanism, highlighting new opportunities for therapeutic intervention.
China's dams threaten green peafowl Tang, Wangwang; Wang, Xiangxi; Yan, Ming ...
Science (American Association for the Advancement of Science),
06/2019, Volume:
364, Issue:
6444
Journal Article
Herpes simplex viruses (HSVs) cause human oral and genital ulcer diseases. Patients with HSV-2 have a higher risk of acquiring a human immunodeficiency virus infection. HSV-2 is a member of the ...α-herpesvirinae subfamily that together with the β- and γ-herpesvirinae subfamilies forms the Herpesviridae family. Here, we report the cryo-electron microscopy structure of the HSV-2 C-capsid with capsid-vertex-specific component (CVSC) that was determined at 3.75 Å using a block-based reconstruction strategy. We present atomic models of multiple conformers for the capsid proteins (VP5, VP23, VP19C, and VP26) and CVSC. Comparison of the HSV-2 homologs yields information about structural similarities and differences between the three herpesviruses sub-families and we identify α-herpesvirus-specific structural features. The hetero-pentameric CVSC, consisting of a UL17 monomer, a UL25 dimer and a UL36 dimer, is bound tightly by a five-helix bundle that forms extensive networks of subunit contacts with surrounding capsid proteins, which reinforce capsid stability.
PDF
