The long range goal is to study virus structure at high resolution, in order to describe mechanisms for viral entry and assemble and to provide a basis for drug and vaccine design. The proposal includes work on three important groups of animal viruses. (1) Crystallographic work on murine polyomavirus will be extended to include a series of virus/oligosaccharide-receptor complexes and to a strain with altered virulence. The results will bear on broad issues of cell attachment and host susceptibility. Structural studies of isolated polyoma VP1 pentamers, alone and in complex with fragments of VP2/3, will also be pursued. (2) Crystallographic analysis of rotavirus single-shelled particles (SSPs) will be carried out, with the goal of a full polypeptide chain trace, building on initial success at low resolution. The organization of these particles represents a new level of complexity for virus crystallography, and the structure bears on issues of viral assembly and maturation as well as on the role of SSPs as 'molecular machines' that transcribe and modify viral mRNA. Complexes of the SSP with the viral ER receptor, NS28, will also be examined. (3) A high resolution (2A) structure of the tick-borne encephalitis envelope glycoprotein will be completed. This is the first flavivirus glycoprotein to be studied crystallographically. recombinant, soluble forms of other flavivirus glycoproteins will be expressed, in order to facilitate comparative studies and the provide an approach to crystallizing PrM/E complexes. The results will advance understanding of enveloped viruses and will be of direct relevance to development of flavivirus vaccines. (4) Work will continue on the methodology of virus crystallography, in order to simplify future efforts.
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| Chao, Luke H; Jang, Jaebong; Johnson, Adam et al. (2018) How small-molecule inhibitors of dengue-virus infection interfere with viral membrane fusion. Elife 7: |
| Salgado, Eric N; Upadhyayula, Srigokul; Harrison, Stephen C (2017) Single-particle detection of transcription following rotavirus entry. J Virol : |
| Harrison, Stephen C (2017) Protein tentacles. J Struct Biol 200:244-247 |
| Kim, Irene S; Jenni, Simon; Stanifer, Megan L et al. (2017) Mechanism of membrane fusion induced by vesicular stomatitis virus G protein. Proc Natl Acad Sci U S A 114:E28-E36 |
| Harrison, Stephen C (2015) Viral membrane fusion. Virology 479-480:498-507 |
| Mahmutovic, Selma; Clark, Lars; Levis, Silvana C et al. (2015) Molecular Basis for Antibody-Mediated Neutralization of New World Hemorrhagic Fever Mammarenaviruses. Cell Host Microbe 18:705-13 |
| Abdelhakim, Aliaa H; Salgado, Eric N; Fu, Xiaofeng et al. (2014) Structural correlates of rotavirus cell entry. PLoS Pathog 10:e1004355 |
| Chao, Luke H; Klein, Daryl E; Schmidt, Aaron G et al. (2014) Sequential conformational rearrangements in flavivirus membrane fusion. Elife 3:e04389 |
| Estrozi, Leandro F; Settembre, Ethan C; Goret, Gaël et al. (2013) Location of the dsRNA-dependent polymerase, VP1, in rotavirus particles. J Mol Biol 425:124-32 |
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