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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