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Acta Cryst. (1993). D49, 355

Protein structure - new approaches to disease and therapy

By Max Perutz

Pp. 326. Oxford, New York: W. H. Freeman, 1992
Price £32.95 (hardcover), £21.95 (paperback). ISBN 0-7167-7021-0 (hardcover), 0-7167-7022-9 (paperback)

The fertile and creative mind of Max Perutz has given the world yet another treasure. This copiously illustrated little book provides a fresh and compelling look at the practical benefits of our rapidly expanding knowledge of protein structures. As Perutz notes in the preface, `The first protein structures revealed wonderful new faces of nature, but they did not help to cure anyone.' The turning point - for Perutz - was the report in 1988 that prolonged remissions had been induced in two terminally ill leukemia patients by humanized rat anti-T-cell antibodies (developed by Herman Waldmann and Gregory Winter). The successful engineering of the crucial antibodies depended, as Perutz points out, on X-ray crystallographic analysis of immunoglobulin structures. In recent years, the number of protein structures solved annually has risen exponentially and, as Perutz notes, the value to medicine of many of these structures only became apparent after their solution. In `Protein Structure,' Perutz celebrates the coming of age of protein crystallography by describing how protein structures are determined and how these studies have revolutionized the treatment of disease.

The first chapter presents a unique nonmathematical description of X-ray crystallography and its application to protein structural determinations. Subtitled `Diffraction Without Tears,' it is a masterful presentation of the fundamentals of crystallography. For those more comfortable with mathematics, the first appendix of the book provides a concise yet complete discussion of the requisite mathematical principles.

Chapter 2, titled `How Proteins Recognize Each Other,' surveys some of the most interesting and timely examples of protein-protein interactions, including antigen-antibody association, recognition of the major histocompatibility complex with T-cell receptors, CD4-HIV interactions, heat-shock proteins and chaperones. This is followed by chapters on protein interactions with DNA and RNA (emphasizing the roles of proteins in transcription) and the binding of drugs to proteins and nucleic acids. Chapter 5 discusses the role of protein structure determinations in drug design, including an account of the computer-based search of the Cambridge Structural Database for compounds complementary in structure to the active site of HIV-1 protease, the resulting identification of bromoperidol and its subsequent use as a model for the synthesis of HIV-1 protease inhibitors.

Chapter 7 describes the role of gene technology in optimization of protein function. One of the examples cited here is that of insulin, which normally exists as a hexamer, but which must dissociate into monomers in order to bind to insulin receptors and thus regulate serum glucose levels. Slow dissociation of insulin hexamers is responsible for the slow action of subcutaneously injected insulin, but the Danish pharmaceutical firm Novo is presently testing a genetically engineered mutant insulin which dissociates to monomers more effectively, due to electrostatic repulsion between subunits arising from the substitution of an aspartate (for proline) at the subunit interface. As Perutz points out, knowledge of the three-dimensional structure of oligomeric insulin was instrumental in the engineering of this faster-acting insulin.

Chapter 8, on virus structure and vaccine engineering, and Chapter 9, describing cytokines, growth factors and differentiation factors, are both excellent. Historical accounts and anecdotes are deftly intertwined with Perutz's lucid descriptions of scientific discovery. One of the best of these is the story of Rita Levi-Montalcini, Stanley Cohen and the serendipitous discovery of nerve growth factor in the snake venom which they were using to try to degrade (the same) nerve growth factor in mouse tumor extracts.

Chapter 10 consists of a table of `Some Medically Important Protein Structures Not Discussed in the Preceding Chapters.' It is clearly the book Perutz was tempted to write as a sequel to the present one, and it makes good reading by itself.

Perhaps the only fault one might find with this lovely book is a minor typesetting flaw. Some of the headings of sections within chapters are in bold type, whereas others are italicized, and there is no apparent pattern to these headings which correlates with the table of contents. It might be added that the italicized headings do not stand out well from the body of the text, and bold type might have been preferable throughout.

Protein Structure by Max Perutz is a special contribution from a very special man. Researchers, teachers and students will all find much to enjoy in this book and, for most, it will enhance and broaden their awareness of the modern impact of protein structure information. It is essential reading for anyone working in protein structure, and it is sure to inspire a generation of younger crystallographers and biochemists.

Charles M. Grisham

Department of Chemistry
University of Virginia
Charlottesville
VA 22901, USA


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