The novel asymmetric entry intermediate of a picornavirus captured with nanodiscs

Hyunwook Lee, Kristin L. Shingler, Lindsey J. Organtini, Robert E. Ashley, Alexander M. Makhov, James F. Conway, Susan Hafenstein

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41 Scopus citations


Many nonenveloped viruses engage host receptors that initiate capsid conformational changes necessary for genome release. Structural studies on the mechanisms of picornavirus entry have relied on in vitro approaches of virus incubated at high temperatures or with excess receptor molecules to trigger the entry intermediate or A-particle. We have induced the coxsackievirus B3 entry intermediate by triggering the virus with full-length receptors embedded in lipid bilayer nanodiscs. These asymmetrically formed A-particles were reconstructed using cryo-electron microscopy and a direct electron detector. These first high-resolution structures of a picornavirus entry intermediate captured at a membrane with and without imposing icosahedral symmetry (3.9 and 7.8 Å, respectively) revealed a novel A-particle that is markedly different from the classical A-particles. The asymmetric receptor binding triggers minimal global capsid expansion but marked local conformational changes at the site of receptor interaction. In addition, viral proteins extrude from the capsid only at the site of extensive protein remodeling adjacent to the nanodisc. Thus, the binding of the receptor triggers formation of a unique site in preparation for genome release.

Original languageEnglish (US)
Article numbere1501929
JournalScience Advances
Issue number8
StatePublished - Aug 2016
Externally publishedYes

Bibliographical note

Funding Information:
We thank P. Tattersall and S. Cotmore of Yale and P. Freimuth of Brookhaven for providing the CAR expression cells. Funding: This work was supported in part by the Pennsylvania Department of Health CURE (Commonwealth Universal Research Enhancement Program) funds. This study was also supported by the Office of the Director, NIH, under award nos. S10OD019995 (to J.F.C.) and S10OD011986 (to S.H.), as well as NIH grants R01AI107121 (to S.H.) and T32CA060395 (to K.L.S.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH

Publisher Copyright:
© 2016 The Authors.


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