Crystal Structure of Human Enterovirus 71

Plevka, Pavel; Perera, Rushika; Cardosa, Jane; Kühn, Richard; Rossmann, Michael G.

doi:10.1126/science.1218713

Cited by 185 publications

(179 citation statements)

References 15 publications

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“…The structures of different strains of EV71 have been determined (20)(21)(22). By comparing the structures of the mature virion and a naturally occurring empty particle (sedimentation coefficient of 80S), Wang et al proposed a sensor-adaptor mechanism for EV71 uncoating (21) and found that the largest movement of the polypeptide occurs in residues 230 to 233 of VP1 at the end of the GH loop and at the beginning of strand H. They referred to this polypeptide region as the adaptor-sensor, which is directly downstream of a region of the GH loop that is external and structurally variable in poliovirus (21).…”

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confidence: 99%

Human Enterovirus 71 Uncoating Captured at Atomic Resolution

Lyu

Ding

Han

et al. 2014

J Virol

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Human enterovirus 71 (EV71) is the major causative agent of severe hand-foot-and-mouth diseases (HFMD) in young children, and structural characterization of EV71 during its life cycle can aid in the development of therapeutics against HFMD. Here, we present the atomic structures of the full virion and an uncoating intermediate of a clinical EV71 C4 strain to illustrate the structural changes in the full virion that lead to the formation of the uncoating intermediate prepared for RNA release. Although the VP1 N-terminal regions observed to penetrate through the junction channel at the quasi-3-fold axis in the uncoating intermediate of coxsackievirus A16 were not observed in the EV71 uncoating intermediate, drastic conformational changes occur in this region, as has been observed in all capsid proteins. Additionally, the RNA genome interacts with the N-terminal extensions of VP1 and residues 32 to 36 of VP3, both of which are situated at the bottom of the junction. These observations highlight the importance of the junction for genome release. Furthermore, EV71 uncoating is associated with apparent rearrangements and expansion around the 2-and 5-fold axes without obvious changes around the 3-fold axes. Therefore, these structures enabled the identification of hot spots for capsid rearrangements, which led to the hypothesis that the protomer interface near the junction and the 2-fold axis permits the opening of large channels for the exit of polypeptides and viral RNA, which is an uncoating mechanism that is likely conserved in enteroviruses. IMPORTANCE Human enterovirus 71 (EV71) is the major causative agent of severe hand-foot-and-mouth diseases (HFMD Human enterovirus 71 (EV71) is the leading causative agent for severe hand-foot-and-mouth diseases (HFMD) in infants and young children (1), and EV71 infection has caused significant morbidity and mortality in the Asia-Pacific regions. During 2008 to 2012, numerous outbreaks of HFMD occurred in mainland China, with over 2,000 fatal cases reported (www.chinacdc.cn). However, vaccines and effective drugs remain unavailable. EV71 belongs to Enterovirus species A within the Enterovirus genus of the Picornaviridae (2). The EV71 virion contains a singlestranded positive-sense RNA genome of 7.5 kb. The viral capsid, which has a diameter of approximately 300 Å, is composed of 60 copies each of VP1 to VP4 (3, 4) that are organized onto a quasi-Tϭ3 icosahedral lattice. The capsid proteins VP1, VP2, and VP3 each possess a ␤-sandwich jelly roll fold and form the outer surface of the capsid shell, whereas VP4 is situated inside the shell. The capsid surface is characterized by a depression encircling each 5-fold symmetry axis, which is referred to as the "canyon" and often contains the receptor-binding site in picornaviruses (5, 6). The hydrophobic pocket of VP1, which is located at the bottom of the canyon, contains a lipid moiety termed the "pocket factor," which likely stabilizes the mature virion. As observed in poliovirus and certain picornaviruses, receptor bindin...

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confidence: 99%

Human Enterovirus 71 Uncoating Captured at Atomic Resolution

Lyu

Ding

Han

et al. 2014

J Virol

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“…There is a circular depression or "canyon" around each icosahedral fivefold axis of symmetry on the surface of many picornaviruses (3,4). The EV71 canyon is shallower than that in polioviruses and rhinoviruses (5,6).…”

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Structure of human enterovirus 71 in complex with a capsid-binding inhibitor

Plevka

Perera

Yap

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Human enterovirus 71 is a picornavirus causing hand, foot, and mouth disease that may progress to fatal encephalitis in infants and small children. As of now, no cure is available for enterovirus 71 infections. Small molecule inhibitors binding into a hydrophobic pocket within capsid viral protein 1 were previously shown to effectively limit infectivity of many picornaviruses. Here we report a 3.2-Å-resolution X-ray structure of the enterovirus 71 virion complexed with the capsid-binding inhibitor WIN 51711. The inhibitor replaced the natural pocket factor within the viral protein 1 pocket without inducing any detectable rearrangements in the structure of the capsid. Furthermore, we show that the compound stabilizes enterovirus 71 virions and limits its infectivity, probably through restricting dynamics of the capsid necessary for genome release. Thus, our results provide a structural basis for development of antienterovirus 71 capsid-binding drugs.stability | virus

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“…Recently, we and others have reported the structures of the virion, the naturally occurring empty particle, an uncoating intermediate or the A-particle, and the empty particle after the uncoating of EV71 as determined by x-ray crystallography or cryo-EM techniques (17)(18)(19)(20)(21). Despite its elusive role during the viral life cycle, the empty particle shares similar structural features with the virion and the uncoating intermediate.…”

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Crystal Structures of Enterovirus 71 (EV71) Recombinant Virus Particles Provide Insights into Vaccine Design

Lyu

Wang

et al. 2015

Journal of Biological Chemistry

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Background:No HFMD vaccine is available. Results: Structures of EV71 recombinant virus particles were determined showing that the inserted foreign peptide is exposed on the particle surface without capsid structural changes and that virus uncoating is not affected. Conclusion: VP1 BC loop is suitable for foreign peptide insertion for the generation of recombinant EV71 viruses. Significance: The results provide insights into vaccine development.

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Crystal Structure of Human Enterovirus 71

Cited by 185 publications

References 15 publications

Human Enterovirus 71 Uncoating Captured at Atomic Resolution

Human Enterovirus 71 Uncoating Captured at Atomic Resolution

Structure of human enterovirus 71 in complex with a capsid-binding inhibitor

Crystal Structures of Enterovirus 71 (EV71) Recombinant Virus Particles Provide Insights into Vaccine Design

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