PROTEINS: Structure, Function, and Genetics 24:i-ii (1996)

THE EDITOR’S CORNER

Happy Birthday Michael Rossmann On 21 October, 1995, about 150 friends and col-

leagues gathered at Purdue University to attend an all-star symposium marking the 65th birthday of Michael Rossmann-and a social event in which Michael was roasted. As one of the founding fathers of protein crystallography, Michael has made major and continuing contributions both to the theoretical and experimental aspects of the field, and to the structural biology of the systems his laboratory has studied. In addition, alumni of his laboratory hold major academic and industrial posts around the world. It is no wonder that many of the attendees came from great distances.

Perhaps the most generally applied of Michael’s methodological advances is molecular replacement. (It is perhaps no coincidence that MR stands for both his name and his method.) In molecular replacement one attempts to solve the crystal structure of a mol- ecule of interest (the target) by a short cut, using a known molecular structure that is a homolog of the target molecule as a probe. An example is to use the structure of one globin to facilitate the structure de- termination of another. Search techniques are used to orient and position the probe molecule within the unit cell of the crystal, so that it maximally overlaps the target molecule. The search thus creates an ini- tial model in which a slightly incorrect molecule ap- pears in the correct place in the unit cell. The model is then refined to produce a bias-free structure of the target. The rotational search method was laid out in a classic paper with David Blow in 1962. Michael also made seminal contributions to the translation problem. In a closely related effort Michael pio- neered phase refinement and extension by the use of redundant information available when a molecule contains noncrystallographic symmetry, or when it crystallizes in more than one space group.

One of Michael’s most important observations in structural and evolutionary biology was the discov- ery of the common nucleotide binding motif now termed the “Rossmann fold.” Indeed, this writer was standing next to Michael in the small alpine village of Alpbach when he first realized, while staring at a model, that this motif occurred in a number of quite different proteins; little did he know how many. The idea that a structural motif could occur in a variety of apparently unrelated proteins was met (to use a gentle term) with skepticism, and only gradually gained acceptance.

For the last fifteen years the Rossmann laboratory has been engaged in the study of spherical RNA vi- ruses. Not long after Stephen Harrison’s laboratory published the first high resolution virus structure, of tomato bushy stunt virus, Michael’s laboratory completed the structure of southern bean mosaic vi- rus a t 2.SA resolution. It was immediately obvious that the protein coat subunits of the two viruses were very similar in structure. Many of the required data were collected from virus crystals with great radiation sensitivity. One could obtain only a single exposure per crystal. Michael named this the “American method”-shoot first and ask questions later.

The laboratory moved to the study of human rhino virus: a picornoviral pathogen responsible for the common cold. The structures of three strains of the virus have been determined at high resolution. The observation that antibody binding sites on the virus map to ridges or exposed loops on the surface led to the “canyon” hypothesis, which suggested that the receptor binding sites are in surface canyons too narrow for an Fab to bind to. Thus receptor binding sites evade the immune system.

The group has now carried the structures of many other viruses, including: Sindbis virus core protein; canine parvovirus; +x 174, a DNA bacteriophage; and Mengo virus. The laboratory is also making rapid progress on the structure of the AIDS virus core protein.

The luster of the symposium was appropriate to the occasion. The leadoff speaker was Nobel Laure- ate William Lipscomb from Harvard, who was Michael’s post-doctoral advisor. Bill spoke on the history of the aspartate transcarbamoylase project and on more recent work on a number of other al- losteric enzymes. He was followed by another Nobel laureate, Robert Huber from the Max Planck Insti- tute for Biochemistry in Munich. Robert covered an enormous number of protease structures his labora- tory has carried out, including the proteosome and the cathepsins.

David Davies told of the long, difficult, but ulti- mately fruitful efforts of his laboratory to crystallize the integrase from HIV. This is the molecule respon- sible for splicing the viral genome into the host cell chromosome, and is critical therapeutic target. Stephen Harrison concluded the morning session with a talk, illustrated with breathtaking graphics,

0 1996 WILEY-LISS. INC.

.. 11 EDITORS CORNER

about viral entry into cells. In the afternoon Roland Rueckert, Michael’s long-time collaborator on the rhinovirus work, gave us the history of the develop- ment of the project and of their work together. The last speaker, appropiately, was Michael, who con- cluded with a description of recent virus structural studies in the laboratory.

The deep affection and respect in which Michael is held, both by current and former laboratory mem- bers and by his collegues elsewhere, was patent. Even those designated to roast him after dinner were rather ineffective. Jack Johnson suggested

that much of Michael’s success could be explained by his child-like approach to science. This is hardly a knock. Who among us would not like to retain imag- inative curiosity, youthful enthusiasm, and a sense of wonder about the marvels of science throughout a long career? After 36 years in structural biology Michael seems as energetic and inventive as ever. The next three dozen years will no doubt be even more productive than the last.

Eaton E. Lattman Editor-in-C hief