Mumps virus 3d

The interaction network was overall conserved; the Neu5Ac carboxylate engaged electrostatic interactions with the receptor Arg, Arg and Arg; Glu, Glu, and Tyr binding pocket residues were also interacting with sialic acid unit. Moreover, the Glc moiety of the trisaccharide formed hydrophobic interactions with Tyr and Val residues; this latter residue was also in close contact with Gal moiety.

The superimposition of the best selected binding mode of both ligands is shown. The parameters of the best models, calculated by Autodock, are also enlisted. The main amino acid residues involved in the binding are indicated as lines. The residues shown are involved into hydrophobic and polar interactions with the ligand.

Hemagglutinin-Neuraminidase activity is essential for the infection and propagation of viruses belonging to the Paramyxoviridae family, including parainfluenza hPIV , the Newcastle disease and mumps viruses. Over the past years, different series of inhibitors have been developed toward viral neuraminidases, especially targeting hPIVs. However, the design and development of novel inhibitors and high-affinity ligands could prove worthwhile for a better understanding of virus tropism and pathogenesis and may help in the fight against viral infections allowing the advancement of new licensed anti-viral drugs.

Here we focused our attention on mumps virus, the leading cause of the mumps disease that could affect the central nervous system, causing meningitis. Mumps virus possesses different surface glycoproteins and among them, the HN represents a multitasking protein mediating both the early and late stages of viral infection, including the host-cell sialoglycans recognition, the trigger of virus and host-cell membranes fusion and finally the release of progeny virions from infected cells.

MuV-HN thus represents an attractive target for the structure-based design and development of novel anti-viral drugs since interfering with these processes may affect the viral pathogenicity and infectivity. Thus, we investigated the structural features of MuV-HN from SBL-1 strain when bound to host-cell sialoglycans with the aim to exploit them as basis for the guided development of tailored inhibitors.

Notably, the kinetic parameters obtained by the elaboration through the Lambert W function were in the same range of the values obtained for the same ligand interacting with MuV-HN from Hoshino strain, as shown in our previous work Forgione et al.

The homology modelling of the protein was also carried out with the aim to achieve a 3D view of the protein-ligand complex. The crystal structure of MuV-HN from the Hoshino strain was used for building the model; that revealed a huge similarity between the 3D structures. It is worth to note that, from the sequence analysis of the two proteins, few variable positions were observed.

This variation was already suggested to be significant for altered antibody recognition and neutralization by MuV-HN Gouma et al. Notably, the neuraminidase binding site was preserved, differently with respect to that observed when comparing the sequences of other MuV-HN genotypes Gouma et al. Our results demonstrated that the main interactions involving the three sugars of the glycan receptor observed when bound to MuV-HN from Hoshino strain were completely conserved in the binding with MuV-HN from SBL-1 strain.

We indeed observed that the Neu5Ac residue was deeply located in the receptor pocket where it established strong polar interactions with the canonical neuraminidases sialic acid recognizing residues, including the Arginine triad Arg, Arg, Arg Interestingly, the MD simulation studies performed on the apo and bound forms of MuV-HN revealed the stabilization of particular inter- strand- and inter-sheet loops upon the ligand binding, thus suggesting that the receptor loop flexibility may play a relevant role in the molecular recognition of sialoglycans by mumps virus hemagglutinin neuraminidase and mechanism of catalysis as well.

Previous studies on the conformational behavior of other neuraminidases Winger et al. Interestingly, the distance measured between the binding pocket walls showed an increased value for the apo-MuV-HN protein, thus suggesting that also for the mumps virus hemagglutinin neuraminidase the glycan receptor specificity may be tuned by loops flexibility. The distances between the walls of the binding site are The main interactions mostly involved the Neu5Ac unit, that interacted with the characteristic receptor binding site amino acids Arg, Arg, Arg, Glu and Tyr Accordingly, the third sugar exhibited stacking interactions with the Tyr Our analysis demonstrated that, in both cases, the main interactions involving the three sugars of the glycan receptor were also comparable to those observed when investigating MuV-HN from Hoshino strain Kubota et al.

Our outcomes may help in the identification of new inhibitor scaffolds which could prove worthwhile in the fight against mumps virus. AS and RM conceived and designed the project. TH and MK produced the protein. OF and FM performed the synthesis. All the authors wrote, revised, and reviewed the article. Simona Coppola is acknowledged for her contribution in preparation of compound 2. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Altschul, S. Basic Local Alignment Search Tool. Amaro, R. Mechanism of cavity Formation in Influenza Neuraminidase. Aricescu, A. Eukaryotic Expression: Developments for Structural Proteomics.

Acta Crystallogr. D Biol. Case, D. AMBER Google Scholar. Chan, J. Biochemistry 51 1 , — Colman, P. Di Carluccio, C. Donahue, M. MMWR Morb. Forgione, R. Goudar, C. Gouma, S. Hashiguchi, T. Her, C. Jain, A. Data Clustering: A Review. Specifically, raw movie stacks at different tilting angles were aligned and summed with dose weighting under MotionCor2.

Obvious junks were excluded from each particle set. After the second round of 2D classification on each particle set, classes with different tilting angles were combined according to the number of protomers and yielded two new datasets for further 3D refinements: protomer ring N ringp and protomer ring N ringp. A local search on Euler angles was performed to avoid possible local minima pitfall.

The structural analysis including surface electrostatic distribution and structural superimposition was fulfilled in UCSF Chimera Further information on research design is available in the Nature Research Reporting Summary linked to this article. Peer review information Communications Biology thanks the anonymous reviewers for their contribution to the peer review of this work.

Primary handling editors: Janesh Kumar and Anam Akhtar. Peer reviewer reports are available. The online version contains supplementary material available at National Center for Biotechnology Information , U. Journal List Commun Biol v. Commun Biol. Published online Jul 2. Author information Article notes Copyright and License information Disclaimer. Qing-Tao Shen, Email: nc. Corresponding author. Received Jul 1; Accepted Jun This article has been cited by other articles in PMC.

Supplementary Information. Descriptions of Additional Supplementary Files. Abstract Mumps virus MuV is a highly contagious human pathogen and frequently causes worldwide outbreaks despite available vaccines.

Subject terms: Virus structures, Cryoelectron microscopy. Introduction The mumps virus MuV is a member of the order Mononegavirales and causes a contagious disease with symptoms ranging from parotitis to mild meningitis and severe encephalitis 1 — 3.

Results MuV N-RNA rings in different protomers Following the previous protocols 27 , MuV nucleoproteins were expressed in an Escherichia coli system and purified using tandem affinity and gel filtration chromatography. Open in a separate window. Table 1 Cryo-EM data collection and data processing statistics.

Structural plasticity of MuV N-RNA rings Previous structural studies have shown that the number of protomers per turn in a given mononegaviral nucleoprotein is usually fixed. Table 2 Structural parameters of nucleocapsids in the order of Mononegavirales. MuV N-RNA filaments in stacked rings Purified MuV nucleoproteins have strong predilection to assemble into rings, which only enwrap a limited number of nucleotides and are obviously not biologically relevant Fig.

Dense and hyperdense MuV helical nucleocapsids Besides the MuV N ring-stacked , there are two other kinds of helical filaments in different pitches based on the 2D classification Fig. Dense and hyperdense MuV helical nucleocapsids. Structural plasticity of MuV helical nucleocapsids The high-resolution structures of MuV N-RNA rings and helical nucleocapsids offer the opportunity to study the molecular mechanism for structural plasticity.

Structural plasticity of MuV helical nucleocapsids. Trypsin digestion assay MuV N WT was treated with trypsin to test the change from ring-like structures to helical nucleocapsids.

Helical reconstruction Before image processing, raw frames were aligned and summed with dose weighting under MotionCor2. Reporting summary Further information on research design is available in the Nature Research Reporting Summary linked to this article. Supplementary information Peer Review File 1. Supplementary Information 21M, pdf.

Descriptions of Additional Supplementary Files 78K, pdf. Supplementary Movie 1 3. Supplementary Movie 2 40M, mov. Reporting Summary K, pdf. Author contributions N. Competing interests The authors declare no competing interests.

Footnotes Peer review information Communications Biology thanks the anonymous reviewers for their contribution to the peer review of this work. Supplementary information The online version contains supplementary material available at References 1.

Hviid, A. Lancet , — Katie, G. Mumps outbreak among vaccinated university students associated with a large party, the Netherlands, Vaccine 30 , — Amarasinghe GK, et al. Taxonomy of the order Mononegavirales: update Molecular biology, pathogenesis and pathology of mumps virus. Acta Crystallogr. F Struct. Sugita, Y. Nature , — Su Z, et al. Electron cryo-microscopy structure of Ebola virus nucleoprotein reveals a mechanism for nucleocapsid-like assembly.

Wan W, et al. Structure and assembly of the Ebola virus nucleocapsid. Albertini AA, et al. Crystal structure of the rabies virus nucleoprotein-RNA complex. Electron cryotomography of measles virus reveals how matrix protein coats the ribonucleocapsid within intact virions. Natl Acad. Paramyxovirus ultrastructure and genome packaging: cryo-electron tomography of Sendai virus.

Ke Z, et al. Promotion of virus assembly and organization by the measles virus matrix protein. Song, X. Self-capping of nucleoprotein filaments protects Newcastle Disease Virus genome.

Elife 8 , e Structure of the vesicular stomatitis virus nucleoprotein-RNA complex. Gutsche I, et al. Structural virology. Near-atomic cryo-EM structure of the helical measles virus nucleocapsid. Structure of the paramyxovirus parainfluenza virus 5 nucleoprotein-RNA complex. Tawar RG, et al. Crystal structure of a nucleocapsid-like nucleoprotein-RNA complex of respiratory syncytial virus.

Bharat TA, et al. Structural dissection of Ebola virus and its assembly determinants using cryo-electron tomography. However, starting in there has been an increase in mumps cases with several peak years.

From year to year, the number of mumps cases can range from roughly a couple hundred to a several thousand, with majority of cases and outbreaks occurring among people who are fully vaccinated and in close-contact or congregate settings. The mumps virus replicates in the upper respiratory tract and is transmitted person to person through direct contact with saliva or respiratory droplets of a person infected with mumps.

The risk of spreading the virus increases the longer and the closer the contact a person has with someone who has mumps. The infectious period is considered from 2 days before to 5 days after parotitis onset, although virus has been isolated from saliva as early as 7 days prior to and up to 9 days after parotitis onset.

Mumps virus has also been isolated up to 14 days in urine and semen. When a person is ill with mumps, they should avoid contact with others from the time of diagnosis until 5 days after the onset of parotitis by staying home from work or school and staying in a separate room if possible. Mumps complications include orchitis, oophoritis, mastitis, meningitis, encephalitis, pancreatitis, and hearing loss.

Complications can occur in the absence of parotitis and occur less frequently in vaccinated patients. Some complications of mumps are known to occur more frequently among adults than children. Mumps orchitis has not been linked to infertility, but may result in testicular atrophy and hypofertility. However, these complications may be more difficult to recognize and are likely underreported. Cases of nephritis and myocarditis and other sequelae, including paralysis, seizures, cranial nerve palsies, and hydrocephalus, in mumps patients have been reported but are very rare.

Death from mumps is exceedingly rare. There have been no mumps-related deaths reported in the United States during recent mumps outbreaks. Mumps that occurs in pregnant women is generally benign and not more severe than in women who are not pregnant. Like other infections, there is a theoretical risk that mumps during the early months of pregnancy may cause complications. Most studies on the effects of gestational mumps on the fetus were conducted in the s—60s when the disease was more common before mumps vaccine was available.

One study from reported an association between mumps infection during the first trimester of pregnancy and an increase in the rate of spontaneous abortion or intrauterine fetal death 1 , but this result has not been observed in other studies 2. One study of low birth weight in relation to mumps during pregnancy found no significant association 1. While there are case reports of congenital malformations in infants born to mothers who had mumps during pregnancy, the only prospective, controlled study found rates of malformations were similar between mothers who had mumps and those who did not have mumps during pregnancy 3.

Learn more about preventing infections during pregnancy. People who previously had one or two doses of MMR vaccine can still get mumps and transmit the disease. During mumps outbreaks in highly vaccinated communities, the proportion of cases that occur among people who have been vaccinated may be high.