Viruses From Structure to Biology

Solving the Structure of Icosahedral Plant Viruses

The first atomic structure of a virus – tomato bushy stunt virus – determined to 2.9 angstrom resolution was published by Stephen Harrison and his colleagues in 1978. The beginning of this work, however, dates from 1965 when Steve joined Don Caspar’s laboratory as a graduate student to solve the structure of this virus Harrison Oral History

Two years later Rossmann and his collaborators solved the structure of southern bean mosaic virus. The origins of this work went back to the early 60s when Michael Rossmann was at the Cavendish Laboratory in Cambridge, England working on the ideas of non-crystallographic symmetry and are set forth in a paper published with David Blow "The Detection of sub-units within the crystallographic asymmetric unit "published in Acta Crystallographica (15: 24, 1962).
Michael Rossmann Oral History

Now there were structures – not diffraction patterns. Did anyone notice? Did information about these structures influence virological research?  

The structure of tomato bushy stunt virus (TBSV) at 2.9 angstroms did change Steve's thinking. He wrote in the Nature (276:368-373,1978) paper "The most remarkable aspect of the TBSV subunit is the configuration of its N-terminal portion". And this was later amplified by "A portion of the polypeptide chain near the N terminus interdigitates with others in an unusual fashion in one state of the subunit (C) and appears disordered in the other, quasi-equivalent positions (A/B). Moreover, RNA appears not to bind to the rigidly-anchored S domain; it may instead interact with the flexibly-linked arms". And in 1999, he remembered "I had just proved for the first time that proteins had dramatic arms and that therefore certainly changed my concept of how proteins work - seeing that arm, because arms just weren't things that we had ever seen. Proteins had these big long arms that would be disordered except when they became part of a more complex structure." Harrison Oral History

A second major impact was the conclusion that there was no well-ordered RNA in the structure. Based on the earlier maps, Steve had suggested that a stretch of density that had no quasi-equivalent partner might correspond to RNA. In 1978, in the Nature paper the conclusion was that "equivalent subunits do not necessarily see RNA in the same position or orientation". And in 1999 Steve recalled that "I realized that this thing had evolved as a package not to care. That it was actually evolutionarily terribly important that it not care at all about where there were stems and loops and things because the RNA needed to evolve and even minor changes in the polymerase sequence would almost certainly change dramatically the stability of particular stems and loops" Harrison Oral History

In 1980 the structure of southern bean mosaic virus was solved to 2.8 angstroms by Michael Rossmann's group at Purdue. The authors of the Nature paper(Vol 286:33-39, 1980) wrote: "The most surprising aspect in the present report is the observation that, in spite of the obvious differences in physical characteristics, the structure of SBMV is closely related to that of TBSV". Rossmann Oral History They also point out "The close similarity between SBMV and the S domain of TBSV strongly supports divergence of these two viruses from a common ancestor."

It appears that notice was taken of the evolutionary implications. Nature had requested a commentary and Steve Harrison wrote "Virus Crystallography Comes of Age". In addition to reiterating the surprising conclusion that SBMV was so similar to TBSV, he also brings up a different issue. He wrote "SBMV and TBSV show quite dramatically that the spatial arrangement of modules in a subunit protein is characteristic of the assembly, but not necessarily of the isolated polypeptide; the remarkable interdigitation of N-terminal arms could not have been anticipated (or even seen) in the structure of the subunit alone." He worries that "high resolution structures of large assemblies may not be readily constructed from structures of component parts". He does point out, however, that there is a "converse advantage of flexibly-linked modules: in cases where function is a property of a particular module of a large protein, proteolytic dissection and piecewise crystallization is a fruitful and helpful strategy" and cites as an example the ability to determine the structure of the soluble form of the influenza virus hemagglutinin - a protein that lacks both the membrane-spanning and C-terminal domains. He could not have anticipated that subsequently the determination of the structure of a fragment of the hemagglutinin would be able to establish how dramatic the changes in the molecule actually are after it is exposed to the pH of membrane fusion.(See the influenza virus hemagglutinin).

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| Introduction | Some historical highlights: structural virology and virology |
| Solving the Structure of Icosahedral Plant Viruses | Picornavirus Structure | Poliovirus | Polio
The Influenza Virus Hemagglutinin
| The Influenza Virus Neuraminidase |
Issues of Science and Society |contributors|
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