Macromolecular Crystals in the Service of Biotechnology and Medicine
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Macromolecular Crystals in the Service of Biotechnology and Medicine
Alexander McPherson University of California, Irvine Dept. of Molecular Biology and Biochemistry Irvine, CA 92697 ABSTRACT The application of genetic and molecular biological methods to the engineering of proteins, the engine of the biotechnology revolution, has become increasingly dependent on knowledge of protein, nucleic acid and virus molecular structure. Structural information of high precision, essential to this enterprise, can only be obtained through X-ray crystallographic techniques. The quality of this information is directly a function of the properties and degree of perfection of the crucial intermediates, the macromolecular crystals. As a consequence, there is now broad and intense interest in developing new methods, procedures and reagents for the nucleation and growth of such crystals. There is, in addition, an expanded interest in the properties of biological crystals and the use of physical measurements in improving approaches to growing better and larger crystals. Here some of the fundamentals of macromolecular crystal growth will be reviewed, and some current trends in the field remarked upon, including the new initiative to develop a national structural genomics program. INTRODUCTION Progress in molecular biology and its application to human medicine, agriculture, and industrial processes have for the past two decades been crucially dependent on knowledge of macromolecular structure at the atomic level, and this has included proteins, nucleic acids, viruses, and other large macromolecular complexes and assemblies. Redundancies of structural elements now emerging from more recently determined molecular structures suggests that the number of structural motifs and substructures (domains) naturally occurring may be finite, and that ultimately all macromolecular structures may be classified and catalogued according to polypeptide folds. Once all, or most of the folds which are utilized by nature are known, then this will provide predictive insight, based primarily on amino acid sequence, of the structures and functions of unknown proteins. The sequences of most proteins, it is important to note, are currently being defined by a broad array of sequencing efforts, such as the human genome project, carried out by both government and the private sector. Extension of these genome projects to the three dimensional structural level appears the next logical step, and this effort, under the broad rubric of structural genomics, is now in the planning stages. In addition to the dramatic impact that knowledge of three dimensional structures of proteins has had on fundamental research in biochemistry and biology, macromolecular structure is of formidable value in biotechnology as well. Here, it provides the essential knowledge required to apply the technique of rational drug design in the creation and discovery of new drugs and pharmaceutical products (McPherson, 1992, 1994). It serves as the basis of powerful approaches now being applied in sma
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